NO134655B - - Google Patents

Description

The present invention relates to an analogous method for the production of hypolipemically active aryloxy and arylthioalkanoic acids, alkali or alkaline earth metal salts or esters or the amide thereof.

Compounds of the general formula I,

where R^ means an alkyl group with at most 14 carbon atoms or a cycloalkyl group with 5-7 carbon atoms,

R.2 hydrogen or the methyl group,

R 2 the hydroxyl group, in which the hydrogen atom can be replaced by an alkali or alkaline earth metal atom, an alkyloxy group with at most 3 carbon atoms or the amino group and

X and Y independently of each other oxygen or sulphur,

are not yet known.

^acUJUtaldMXL..«ftÉL&& J9PmJP* ll9. ,£orrael I, ,as the 2-,(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid, 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)- dodecanoic acid, 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-octanoic acid, 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-dodecanoic acid, 2-(6 ,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-octanoic acid, -•2--(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-dodecanoic acid, 2-(6,7, 8,9-tetrahydro-dibenzofuran-2-ylthio)-octanoic acid, 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-octanoic acid, 2-(6,7,8,9-tetrahydro- the dibenzothiophen-3-ylthio)-octanoic acid and the 2-(6,7,fl,9-tetrahydro-dibenzothiophen-2-ylthiooctanoic acid,

has valuable pharmacological properties and a high therapeutic index. When administered orally, they show particular hypolipemic activity, such as e.g. can be seen by lowering the cholesterol and triglyceride content in blood and liver after several administrations in doses of 2 times lo mg/kg to male rats according to standard methods. According to R. Richterich and K. Lauber (cf. Klin. tfochen-Schrift 40, 1252-1256 (1962)) the total content of cholesterol is determined directly in serum. Furthermore, according to J.Folch et al (comp. J. Biol. Chem. 226, 497 (1957)) both serum and liver lipid are extracted and triglyceride and total cholesterol are determined using the autoanalyzer according to G. Kessler and H. Lederer (comp. Automation in der Analytischen Chemie (1965), Technichon GmbH, Frankfurt/Main, pages 863-872, respectively W.D. Block et al, ibid. pages 97o-971).

The new compounds excel in comparison with the hypolipemic activity at low hepatomegaly activity.

In Norwegian patent application no. 3735/69, 2-(fluoren-2-yloxy)- and 2-(fluoren-2-ylthio)-alkanoic acid and in Norwegian patent application no. 2627/7o are 2-(4b,5,6/7, 8/8a-hexahydrofluoren-2-yloxy)- and 2-(4b, 5,6,7,8,8a-hexahydrofluoren-2-ylthio)-alkanoic acids with cholesterol-lowering properties described. Compared to the above compounds, it has been found that the compounds in the present patent application have equally good or even better cholesterol-lowering properties, to which, according to the present patent application, the compounds have significantly less hepatomegaly effect.;

In the compounds with the general formula I, R means, as an alkyl group with at most 14 carbon atoms, e.g. methyl-, ethyl-, propyl-, butyl-, isobutyl-, pentyl-, isopentyl-, 2,2-dimethyl-propyl-, hexyl-, isohexyl-, 3,3-dimethyl-butyl-, heptyl-, nonyl- , the decyl, undecyl, dodecyl, tridecyl or tetradecyl group and as a cycloalkyl group with 5-7 carbon atoms, e.g. the cyclopentyl, cyclohexyl or cycloheptyl group.

The new compounds with the general formula I are prepared according to the invention in such a way that. one reacts an alkali metal salt of a phenol or thiophenol with the general formula

II,

where X and Y have the meanings given under the general formula I, with a compound of the general formula III,

where R^, R2 and R^ have the meanings given under the general formula I and

A means halogen, an alkylsulfonyloxy- or a

ary1su1phony1oxy group.

The reaction is preferably carried out in a solvent or diluent. Such solvents or diluents are e.g. lower alkanols, such as ethanol, or solvents free of hydroxyl groups, such as N,N-dimethylformamide, N,N-dimethylacetamide or N,N,N',N',,N'',N''-hexamethyl phosphoric acid triamide.

The reaction temperature is between 50 and 15o°, preferably at the boiling point of the solvent used. The boiling temperature, which under normal conditions can be achieved for the solvent, can, if desired, be increased by working in a closed container. The formation of those used as starting materials the alkali salts of phenols or thiophenols of the general formula II, as well as alkali salts of <Xde of the general formula III comprising carboxylic acids, preferably occur in situ, e.g. by means of an alkali metal alcoholate, hydroxide or hydride, depending on whether an anhydrous alkanol or a hydroxyl group-free solvent is used as reaction medium. Instead of an alkali metal hydride, the corresponding amide, e.g. sodium amide, is used.

The phenols used as starting materials according to the invention or thiophenols of the general formula II, namely 6,7,8,9-tetrahydro-dibenzofuran-2-ol, 6,7,8,9-tetrahydro-dibenzofuran-3-ol, 6,7,8,9-tetrahydro-dibenzofuran- 2-thiol, 6,7,8,9-tetrahydro-dibenzofuran-3-thiol, 6,7,8,9-tetrahydro-dibenzothiophen-2-ol, 6,7,8,9-tetrahydrodibenzothiophen-3- ol, 6,7,8,9-tetrahydro-dibenzothiophene-2-thiriL and 6,7,8,'9-tetrahydro-dibenzothiophene-3-thiol can be prepared according to different methods. E.g. 6,7,8,9-tetrahydro-dibenzofuran-2-ol can be easily prepared by reacting 1-morpholino-cyclohexene-(1) and p-benzoquinone at room temperature in methylene chloride and then cleaving the first obtained 5a ,6,7,8,9,9a^hexahydro-5a-morpholino-dibenzo-furan-2-ol by boiling in aqueous hydrochloric acid to 6,7,8,9-tetrahydro-dibenzofuran-2-ol and morpholine hydrochloride [ coll. G. Domschke,. J. Prakt. Chem. 32 144-157 (1966)].

Another possibility for the preparation of 6,7,8,9-tetrahydro-dibenzofuran-2-ol, which simultaneously includes the preparation of ['.'■'■ 6,7,8,9-tetrahydro-dibenzofuran-3-ol, consists in converting^ 2-chloro-cyclohexanone or 2-bromocyclohexanone with an alkali metal salt of the hydroquinone monomethyl ether or the resorcin monomethyl ether, and then transfers the first obtained 2-(4-methoxy-phenoxy)-cyclohexanone or 2-(3-methoxy-phenoxy)-cyclohexanone in the presence of an acidic catalyst, such as e.g. phosphoric acid or sulfuric acid, in 2-methoxy-6,7,8,9-tetrahydro-

respectively 3-methoxy-6,7,8,9-tetrahydro-dibenzofuran, after which the methyl group is split off. The cleavage of the methyl group can

e.g. is made by boiling the compounds in a mixture of conc. hydrobromic acid and glacial acetic acid or by heating with pyridine hydrochloride.

6,7,8,9-tetrahydro-dibenzofuran-2-thiol as well as 6,7,8,9-tetrahydro-dibenzofuran-3-thiol can be obtained in a simple way by starting from the corresponding 2- or The 3-hydroxy compounds, by which these are reacted with an N,N-dialkyl-thiocarbamic acid chloride, rearranges it into 2- or 3-position present N,N-dialkyl-thiocarbamoyloxy group in N,N-dialkyl-carbamoylthio group and then hydrolyzes. The re-laying is suitably carried out by heating the compounds to temperatures of 250 - 300° for several hours [cf. also M.S.Newman and H.A. Kårnes J. Org. Chem. 31, 3980-3984, (1966)].

For the production of 6,7,8,9-tetrahydro-dibenzothiophen-2-ol and 6,7,8,9-tetrahydro-dibenzothiophen-3-ol, e.g.

2-chloro- or 2-bromo-cyclohexanone with an alkali salt of 4-methoxy-

respectively 3-methoxy-thiophenol to 2-(4-methoxy-phenylthio)-cyclohexanone or 2-(3-methoxy-phenylthio)-cyclohexanone, after which these compounds are converted during ring formation with phosphoric acid and ether cleavage with pyridine hydrochloride in 6,7,8,9-tetrahydro-dibenzothiophene-2- or -3-ol. From these compounds, 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 6,7,8,9-tetrahydro-dibenzo-thiophene-3-thiol can be obtained again by reacting N,N-dialkyl -thiocarbamic acid chloride, rearrangement of it in 2- or 3-position present N,N-dialkyl-thiocarbamoyloxy group in the N,N-dialkyl-carbamoylthio group and then hydrolysis [cf. M.S. Newman and H.S. Kårnes, J. Org. Chem. 31, 3980 - 3984,

(1966)] .

Those of the general formula II included and as starting materials necessary phenols and thiophenols of the general formula Ila and ub,

where X and Y have those under the general formula I

stated meanings,

as well as 6,7,8,9-tetrahydro-dibenzofuran-2-thiol are not known to date.

The starting materials with the general formula III, which include the chlorides and bromides derived from 2-hydroxyalkanoic acids, -alkanoic acid esters and -alkanoic acid amides, can be prepared in an analogous way as 2-bromo-propionic acid ethyl ester [cf. Ann. 197, 13

(1879)]. They likewise of the general formula III comprising alkyl or Arylsulfonic acid esters can be prepared by starting from the bromides produced in this way and reacting them

■ with corresponding sulfonic acid salts, or by reacting 2-hydroxyalkanoic acids, esters or amides with an alkyl or

arylsulphonic acid<ft>echloride in the presence of alkali, oc-halocarboxylic acids can further be prepared by the generally known <x-halogenation of carboxylic acids. Starting from these, the corresponding lower alkyl esters and those also of the general formula III comprising amides can be easily prepared according to known methods.

Aryloxy- or arylthioalkanoic acids, which are covered by the general formula I and which have the general formula Ia,

where R^, R£, X and Y have the meanings indicated under the general formula I,

n. , , are produced

or their alkali and alkaline earth metal salts by hydrolyzing or saponifying a functional derivative of such an acid.

As functional derivatives of aryloxy- or arylthioalkanoic acids of the general formula Ia come their esters, e.g.

lower alkyl ester or the cyclohexyl, phenyl or benzyl ester, as well as nitriles, amides and lower imidoalkyl

esters into account. These functional derivatives of carboxylic acids with the general formula Ia can be hydrolysed by heating in an aqueous mineral acid, e.g. by boiling in 60 - 70% sulfuric acid or in a mixture of e.g. 6-n hydrochloric acid and glacial acetic acid. The free carboxylic acids with the general formula Ia obtained by this embodiment can, if desired, be transferred into an alkali or alkaline earth salt. When dilute mineral acid is used in carrying out the method, a solubilizer must be used because the starting material is poorly soluble in water. Current such are

organic solvents such as e.g. lower alkanols, tetrahydrofuran or, as already mentioned, glacial acetic acid. However, the hydrolysis can also be carried out in an alkaline medium, e.g. by heating in an alkanol or aqueous-alkanol alkali hydroxide solution at temperatures between approx. 5.0 and the boiling temperature of the reaction medium used. From the alkali metal salts obtained in this embodiment, the free acids of the general formula Ia can be obtained, if desired. by that

one e.g. dissolves the alkali salts in water and adds mineral acid. The functional derivatives of carboxylic acids with the general formula Ia required as starting materials can be obtained analogously to the first method, by reacting an alkali salt of a phenol or thiophenol of the general formula II with corresponding 2-bromoalkanoic acid esters, -amides and -nitriles. By starting from the nitriles obtained in this way, the imidoalkyl esters that can be used as starting materials can be prepared by reaction with an alkanol in the presence of hydrogen chloride. A further production method for functional derivatives of carboxylic acids with the general formula Ia consists in decarboxylating the monoester or monoamide of correspondingly substituted aryloxy or arylthiomalonic acids or equivalent, substituted aryloxy- or arylthiocyanoacetic acids.

Following a third method according to the invention, aryloxy or arylthio-alkanoic acids of the general formula Ib,

where R1? X and Y they have under the general formula I

stated meanings,

and their salts with alkali or alkaline earth metals, by heating compounds of the general formula IV,

where R^, X and Y have the meanings given under formula I, and

Z 1 and Z 2 independently of each other mean lower alkoxy carbonyl or nitrile groups,

until one of the groups Z₂ or Z₂ is cleaved off and the other is converted to a carboxyl group or an alkali or alkaline earth metal salt thereof.

According to an embodiment according to this invention, compounds with the general formula IV are heated in an aqueous mineral acid, e.g. 60 - 70% sulfuric acid or conc. hydrochloric acid, and transfer the obtained carboxylic acid of the general formula Ib, if desired, into an alkali or alkaline earth salt. Optionally, the reaction can take place in the presence of an inert and water-miscible organic solvent, which serves as a dissolution agent for the starting substances that are difficult to dissolve in water. Such solvents are used, e.g. lower alkanols, tetrahydrofuran, glacial acetic acid, etc.

According to a further embodiment according to the invention, compounds of the general formula IV are heated with alkanol-containing alkali hydroxide, e.g. methanolic potash or in aqueous alkanol alkali hydroxide, and transfer the thus obtained alkali salts of the carboxylic acids of the general formula Ib, if desired, into the free acids. By carrying out the process in an alkaline environment, mixtures can sometimes be obtained in which, in addition to the desired end products,

incompletely saponified and incompletely decarboxylated intermediates are still present. These can by subsequent heating with an aqueous mineral acid, and "possibly in the presence

of a water-miscible organic solvent according to the first embodiment of the method, is transferred into uniform aryloxy- or arylthioalkanoic acids of the general formula Ib. To carry out the method, substituted malonic acid dialkyl esters with the general formula IV are boiled for a few hours

under reflux in the aforementioned reaction medium. So did they

under the general formula IV, the malonic acid dinitriles and the corresponding cyanoacetic acid esters are reacted analogously, whereby these usually require stronger reaction conditions and a longer reaction time. In that case, the reaction according to the invention can, if necessary, be carried out in a closed reaction vessel under pressure.

The under the general formula IV sorting 6,7,8,9-tetrahydro-dibenzofuran-2-yloxy-, 6,7,8,9-tetrahydro-dibenzofuran-3-yloxy-, 6,7,8,9- tetrahydro-dibenzofuran-2-ylthio-, 6,7,8,9-tetrahydro-dibenzofuran-3-ylthio-, 6,7,8,9-tetrahydro-dibenzothio-phen-2-yloxy-, 6,7,8 ,9-tetrahydro-dibenzothiophen-3-yloxy-, 6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio- and 6,7,8,9-tetrahydro-dibenzo-thiophen-3-ylthiomalonic esters malonic nitriles and

-Cyanoacetic acid alkyl esters, on the other hand, are new compounds.

They can e.g. obtained by reacting alkali salts of 6,7,8,9-tetrahydro-dibenzofuran-2-ol, 6,7,8,9-tetrahydro-dibenzofuran-3-ol, 6,7,8,9-tetrahydro-dibenzofuran- 2-thiol, 6,7,8,9-tetrahydro-dibenzofuran-3-thiol, 6,7,8,9-tetrahydro-dibenzo-thiophen-2-ol, 6,7,8,9-tetrahydro-dibenzothiophene -3-ol, 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol or 6,7,8,9-tetrahydro-dibenzothiophene-3-thiol, with R^-substituted bromomalonic acid dialkyl esters, bromocyanoacetic acid alkyl esters or bromomalonic acid nitriles. Of the mentioned bromine compounds, some are known, e.g. bromopropryl-malonic acid diethyl ester [cf. A.W. Doc. and L. Joder, J. Am. Chem. Soc. 44, 1578-1581 (1922)]. Further compounds of this type can be prepared analogously.

According to a fourth method according to the invention, the aryloxy or arylthioalkanoic acids, their salts with alkali and alkaline earth metals, their lower alkyl esters and amides of the general formula Ic,

acid, which decomposes between 29o and 3o5° during browning.

To determine the hypolipemic and hepatomegaly effects of the compounds, the following experimental method was used:

Male rats (SIV 5o, 18o-2oo g) are administered orally for four days,

twice daily a corresponding dose/kg body weight of the test substances in 2 ml polyethylene glycol or in 1% aqueous gum arabic. On the fourth day of the trial, a 3rd administration is carried out within hours of the end of the trial. The animals receive a standard diet and food ad libitum. The liner is removed 16 hours before the end of the trial. The animals are killed on the fifth experimental day by decapitation, and blood samples are taken for cholesterol determination and the liver is weighed.

Blood serum and liver are extracted according to Folch (J. Biol.

Chem. 226 , 497, (1957)), and cholesterol is determined using

of the autoanalysis apparatus according to Block et al. (Technico.. Symposium 1965).

The following compounds were tested:

I .2-(Fluoren-2-yloxy)-isoheptanoic acid

II 2-(Fluoren-2-yloxy)-5,5-dimethylhexanoic acid

III 2-(fluoren-2-ylthio)-heptanoic acid

IV 2-(4b,5,6,7,8a-hexahydrofluoren-2-yloxy)-heptanoic acid

V 2-(4b,5,6,7,8,8a-hexahydrofluoren-2-yloxy)-5-methyl-hexanoic acid

VI 2-(4b,5,6,7,8,8a-hexahydrofluoren-2-yloxy)-octanoic acid VII 2-(6,7,8,9-tetrahydrodibenzofuran-2-yloxy)-butyric acid

VIII 2-(6,7,8,9-tetrahydrodibenzofuran-2-yloxy)heptanoic acid

IX 2-(6,7,8,9-tetrahydrodibenzofuran-2-yloxy)-heptanoic acid ethyl ester

X 2-(6,7,8,9-tetrahydrodibenzofuran-2-yloxy)-octanoic acid

XI 2-(6,7,8,9-tetrahydrodibenzofuran-2-yloxy)-octanoic acid amide XIi; 2-(6, 7, 8, 9-tetrahydrodibenzofuran-2->yloxy)-dodecanoic acid XIII 2-(6,7,8,9-tetrahydrodibenzofuran-2-yloxy)-tetradecanoic acid XIV 2-(6,7,8, 9-tetrahydrodibenzofuran-2-yloxy)-hexadecanoic acid in XV 2-(6,7,8,9-tetrahydrodibenzofuran-2-ylthio)-isoheptanoic acid XVI . 2-(6, 7, 8, 9-tetrahydrodibenzofuran-2-ylthio)-octanoic acid XVII 2-(6,7,8,9-tetrahydrodibenzofuran-3-ylthio)octanoic acid XVIII 2-(6,7,8,9- tetrahydrodibenzofuran-3-ylthio)-dodecanoic acid XIX 2-(6,7,8,9-tetrahydrodibenzofuran-3-yloxy)-octanoic acid XX 2-(6,7,8,9-tetrahydrodibenzofuran-3-yloxy)-dodecanoic acid

The compounds I-IIt according to Norwegian patent application no. 3735/69. Compounds IV-VI according to Norwegian patent application no. 26 27/70. The compounds VII-XX according to the present invention.

The following table shows the obtained values.

In relation to the compounds I-VI, the compounds, according to the present patent application, have good or even better cholesterol-lowering properties. However, they stand out compared to the known compounds in particular in that they exhibit a ; significantly less hepatomegaly effect.

where R^, R3, X and Y have the meanings indicated under the general formula I, is obtained by heating a compound of the general formula V, where R^, Rj, X and Y have the meanings indicated under the general formula I , for splitting off the equimolar amount of carbon dioxide. The compounds with the general formula V can either be heated as such or in an inert solvent, e.g. toluene or xylene, to temperatures of 100 - 150°. The compounds with the general formula V can e.g. is produced by completely or partially saponifying the ester of malonic acid or malonamide acid. The malon-amic acid can be obtained by binding water to the nitrile group in the corresponding cyanoacetic acid ester and then immediate saponification of the ester group. For the preparation of alkali salts of carboxylic acids with the general formula Ic, one preferably starts from acid salts of the malonic acid classified under the general formula V, whereby these are heated to split off the equimolar amount of carbon dioxide, and release, if desired, from the obtained salt the under the general formula 1C sorting carboxylic acid. Those under the general formula I sorting aryloxy- or The aryl-thioalkanoic acid amides _with the general formula Id, where R 1 , R 2 , X and Y have the meanings given under them in the general formula I, can be prepared according to a fifth method according to the invention by reacting an aryloxy or arylthioalkanoic acid derivative of the general formula VI,

where R^, R^, X and Y have the meanings indicated under the general formula I and

B means halogen or an alkoxy group,

with ammonia. To carry out the reaction according to the invention, a compound of the general formula VI is preferably dissolved in an inert solvent, and then ammonia is introduced. As a result, acid halides already react at room temperature, while the ammonolysis of the ester usually requires higher temperatures. Relevant solvents for the reaction of the acid halides classified under the general formula VI with ammonia are ether-containing solutions, such as e.g. diethyl etherj tetrahydrofuran, or hydrocarbons, which

e.g. benzene, toluene, etc., or chlorinated hydrocarbons, such as chloroform and methylene chloride. When reacting the esters classified under the general formula VI with ammonia, in addition to the higher ethers and hydrocarbons mentioned, lower alkanols, such as e.g. methanol or ethanol, as suitable solvents. The turnover takes place e.g. by heating with ammonia-saturated solutions of esters in the aforementioned solvents under reflux and, if necessary, under pressure in a closed vessel.

The acid halides with the general formula VI used as starting materials can be obtained by starting from the corresponding carboxylic acids, whereby these are reacted with thionyl chloride or phosphorus pentachloride, phosphorus trichloride or phosphorus oxychloride.

The free carboxylic acids, which form the basis of compounds with the general formula VT, as well as the esters which can be attributed to this formula, can in turn be prepared analogously to the first method by reacting alkali salts of the corresponding phenols or thiophenols with oc-halides of the corresponding alkanoic acids or their lower alkyl esters.

Those under the general formula I sorting aryloxy- or arylthioalkanoic acid amides of the general formula Id, >

where R.p R^, X and Y have the meanings indicated under the general formula I, can be obtained according to a sixth method according to the invention by adding to a nitrile with the general formula VII,

where R2, X and Y have those under the general formula

In the meanings indicated,

binds water. This method can be carried out in such a way that the starting material is nitrite1 with the general formula VII dissolved in a strong mineral acid, e.g. sulfuric acid, which contains a quantity of water sufficient to form an amide, and by stirring the solution for 1/2 to 1 hour at temperatures between 20 and 60°. This reaction can, if desired, also be carried out in the presence of a solvent, e.g. ether or tetrahydrofuran. A further possibility for carrying out the reaction according to the invention consists in dissolving a nitrile of the general formula VII in aqueous ether and introducing hydrogen chloride in gaseous form into this. According to a further variant of the method according to the invention, a nitrile with the general formula VU is reacted in an alkaline medium with hydrogen peroxide. The reaction is carried out in an aqueous solution, whereby care must be taken that this contains a sufficient amount of a water-miscible organic solvent, e.g. a lower alkanol capable of dissolving a nitrile of the general formula VII.

According to another variant of the method according to the invention, a nitrile with the general formula VII is first transferred into imidoalkyl ester hydrochloride by dissolving in an aqueous lower alkanol and under the introduction of hydrogen chloride, after which, by heating to temperatures of 80 - 130°, preferably 90 - 100°, cleaves in an amide of the general formula I d and alkyl chloride.

Those under the general formula I sorting aryloxy- or arylthioalkanoic acid esters of the general formula Ie,

where R^, R2, X and Y have the meanings given under the general formula I and R3' means a lower alkyl residue with 1-3 carbon atoms, according to the invention can be prepared by reacting a nitrile with the general formula VII,

where R^, R2, X and Y have those under the general

formula In the meanings indicated,

in the presence of water and mineral acid with a lower alkanol. Several variants are possible for carrying out the method according to the invention. One can e.g. boiling the nitrile of the general formula VII in the presence of the equimolar amount of sulfuric acid and water with an excess of lower alkanol under reflux. The final product is isolated by diluting the reaction mixture with water, whereby the ester with the general formula I, which is difficult to dissolve in this solution, is precipitated as a crude product. >'

According to a further embodiment of the method according to the invention, the compound can first be converted into imido-ester hydrochloride by reaction with a lower alkanol in the presence of hydrogen chloride, and then hydrolyzed to an ester with the general formula le- The conversion of the nitrile into the imido-ester hydrochloride is carried out preferably in a solvent. As such, one can use e.g. excess amount of

alkanol, ether or chloroform. Finally, water can also be bound to the nitrile with the general formula VII, after which an alcoholysis of the obtained amide is carried out in the presence of a mineral acid. Thereby, the water-anchoring of the nitrile is suitably carried out in 80 - 95% sulfuric acid, after which an excess of alkanol is added to the obtained solution of amide in sulfuric acid. The mixture is then boiled under reflux. Isolation of the end product here is also done most simply by diluting the reaction mixture with water, whereby the desired ester is precipitated as a crude product.

The nitrile with the general formula VTI used as starting material can also be obtained analogously to the first method by reacting an alkali salt of a corresponding phenol or thiophenol with an o-haloalkanoic acid nitrile.

Those under the general formula I sorting aryloxy- or arylthioalkanoic acids, and which also have the general formula Ia indicated above, where R^, R^, X and Y have the meanings indicated under the general formula I, and their salts with alkali metals are prepared according to an eighth method,

by reacting a bis-alkali metal or bis-halo-magnesium compound of a carboxylic acid with the general formula 'VIII,

where X, Y and R2 have those indicated under formula I

meanings,

with the substantially equimolar amount of a compound of the general formula IX,

where R^ has the meaning given under formula I and A means halogen, an alkylsulfonyloxy or an arylsulfonyloxy group,

wherein the acid of formula I is liberated from a compound obtained from the bis-halogen magnesium compound of formula VIII by reaction with an acid. as a bis-alkali metal compound, the bis-lithium compound in particular comes into consideration, and also bis-sodium compounds. E.g. is first formed at approx.

-10° - 0° of diisopropylamine and butyllithium in tetrahydrofuran-hexane mixture the lithium-diisopropylamide, then add carboxylic acid of the general formula VIII and then at least an equimolar amount of hexamethylphosphoric acid triamide, after which the compound of the general formula IX is added and the reaction is completed at room temperature . The addition of hexamethyl phosphoric acid triamide may optionally be omitted, and then especially when using starting materials with a methyl group such as R2-

According to a further embodiment of the method, the sodium amide suspension is formed in liquid ammonia, which in turn was produced in situ from ammonia-containing sodium solution by adding a catalytic amount of iron (III) nitrate while stirring and until the blue color of the metal solution was disappeared, and carboxylic acids of the general formula VIII bis-sodium compounds of the latter, after which these are reacted with compounds of the general formula IX, and which are added dissolved in ether or tetrahydrofuran.

Bis-halogenmagnesium compounds of carboxylic acids with the general formula VIII are obtained, e.g. by reacting these acids with the double molar amount of isopropylmagnesium bromide or isopropylmagnesium chloride in an ethereal solution at room temperature and with a reaction time of approx. 4 - 15 hours. Finally, the reaction with compounds of the general formula IX is preferably also carried out in ether or in another ether-containing solvent, such as e.g. tetrahydrofuran, at a temperature between room temperature and the boiling temperature of the reaction solution.

They use carboxylic acids with the general formula as starting materials. iVIII, where R 2 means eh methyl group, are new substances which sort under the general formula I, and which can be prepared according to one of the above-mentioned methods, and then preferably according to the first or second method.

Those as starting substances under the general formula VIII sorting and necessary carboxylic acids with the general formula Villa,

where X and Y have the meanings given under formula I, are also new substances. They are produced by reacting an alkali metal salt of a compound of the general formula II with a haloacetic acid, analogously to the first method

or a lower haloacetic acid alkyl ester, whereby in the latter case the obtained lower alkyl ester is first hydrolysed analogously to the second method.

In compounds with the general formula IX, A as halogen preferably means bromine, further also iodine or chlorine, as an alkylsulfonyloxy group, e.g. the methanesulfonyloxy group, and as an arylsulfonyloxy group e.g. the p-toluenesulfonyloxy group.

Following a ninth method, the aryloxy or arylthioalkanoic acids of the general formula If,

where X, Y and have the meanings given under formula I, and their salts with alkali and alkaline earth metals, reacting a compound of the general formula II given above, where X and Y have the meanings given there, with one with chlorine and/ or bromo tri- or tetra-substituted methane and a ketone of the general formula X, where R^ has the meaning given under formula I, or with the reaction product of the two latter components, i.e. a compound of the general formula XI,

where R has the meaning given under formula I,

and Hal means chlorine or bromine,

in the presence of at least four times the molar amount of a strong base, after which a salt obtained, which is not an alkali or alkaline earth metal salt, is converted to an alkali or alkaline earth metal salt or then a free acid, and if desired, a free acid obtained is converted to an alkali or alkaline earth metal salt, or an obtained alkali or alkaline earth metal salt is converted into the free acid or another alkali or alkaline earth metal salt. The reaction is preferably carried out in an excess of ketone with the general formula X as reaction medium. Also when starting materials with the general formula XI are used, the corresponding ketone is preferably used as solvent. The reaction temperature is preferably between 0° and the boiling temperature of the ketone used. The latter is preferably acetone, while chloroform is preferably chosen as a halogen-substituted methane derivative, 1,1,1-trichloro-2-methyl-2-propanol as a compound of formula XI and an alkali metal hydroxide, such as sodium or potassium hydroxide, as a strong base. As acetone and other methyl ketones in the presence of these strong bases are known to react with chloroform as well as with other tri- and tetrahalogen methanes, such as e.g. bromoform, carbon tetrachloride and carbon tetrabromide, to compounds with the general formula IX, then in both process variants the same reaction will eventually take place.

As alkali and alkaline earth metal salts of the carboxylic acids classified under the general formula I, e.g. their sodium, potassium-lithiumT magnesium and calcium salts into account. The production of these salts takes place e.g. by mixing acid and base in a suitable solvent, such as methanol, ethanol or acetone-water. The relatively poorly soluble salts obtained can be isolated by filtration, and easily soluble salts can be isolated by evaporation of the 1 osmotic agent. Furthermore, the salts which are poorly soluble in the solvent used can also be prepared in a double reaction of another salt of the acid with the base or a suitable salt of the same.

The following examples illustrate the preparation of compounds of the general formula I and their salts. Temperatures are indicated in degrees Celsius. The term mmol means millimole = 0.001 mol. in naming the compounds produced, the alkyl residues, which deviate from the normal, unbranched chain, are marked by designations such as sec.-, tertiary- or iso-alkyl. If these designations are missing, then the normal, unbranched remainder is always meant.

EXAMPLE 1

4.0 g (21.0 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-2-ol are added to a round-bottom flask with reflux skirts, dropping funnel, potassium hydroxide drying tube, stirrers and gas introduction tube

to a solution of 0.48 g (21.0 mmol) sodium in 50 ml abs. ethanol under a nitrogen atmosphere. To the thus obtained solution of sodium 6,7,8,9-tetrahydro-dibenzofuran-2-olate, 4.98 g (21.0 mmol) of 2-bromoheptanoic acid ethyl ester are added dropwise while stirring and refluxed for 4 hours . After cooling, the reaction mixture is evaporated in a vacuum and the residue is distributed between water and ether. After washing with water to pH = 7 and drying with magnesium sulfate, the ether solution is evaporated, whereby a pale yellow oil is obtained. The crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid ethyl ester, which is still contaminated with 6,7,8,9-tetrahydro-dibenzofuran-2-ol, is purified using column chromatography (neutral silica gel 0.05 - 0.2 mm Merck, solvent benzene). The benzene fractions, which contain the desired esters, are combined and evaporated. After drying in high vacuum, the pure 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid ethyl ester is obtained, a weak

23

yellow pungent oil, n^ : 1.5248.

Analogously, one obtains:

of 4.0 g (21.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 3.8 g (21.0 mmol) 2-bromo-propionic acid ethyl ester 2-(6,7 ,8,9-20 tetrahydro-dibenzofuran-2-yloxy)-propionic acid^ethyl ester, 11 : 1.5408;

of 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 1.95 g (10.0 mmol) 2-bromo-2-methyl-propionic acid ethyl ester 2- (6,7,-8,9-tetrahydro-dibenzofuran-2-yloxy)-2-methyl-propionic acid ethyl ester, n^ : 1.5361;

in

! of 3.76 g (20.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 4.18 g (20.0 mmol) 2-bromo-penta-acid ethyl ester 2-(6,7 ,8,9-tetrahydro-dibenzofuran-2-yloxy)-pentanoic acid ethyl ester, 1.5324;

of 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 2.23 g (10.0 mmol) 2-bromo-heptanoic acid methyl ester 2-(6,7 The ,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid methyl ester,

20

n<£U> : 1.5320;

of 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 2.6 g (10.0 mmol) 2-bromo-heptanoic acid propyl ester 2-(6,7 The ,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid propyl ester, n£<u> : 1.5220;

of 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 2.37 g (10.0 mmol) 2-bromo-isoheptanoic acid ethyl ester 2-(6,7 The ,8,9-tetrahydro-dibenzofuran-2-yloxy)-isoheptanoic acid ethyl ester, n£° : 1.5241;

of 3.76 g (20.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 5.02 g (20.0 mmol) 2-bromo-octanoic acid ethyl ester 2-(6,7 The ,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid ethyl ester,

njf : 1.5219;

of 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 2.79 g (10.0 mmol) 2-bromodecanoic acid ethyl ester 2-(6,7 ,8,9-tetrahydro-dibenzofuran-2-yloxy)-decanoic acid ethyl ester,

n^° : 1.5262;

of 3.0 g (16.0 mmol) 6,7,8g9-tetrahydro-dibenzofuran-2-ol and 4.91 g (16.0 mmol) 2-bromo-dodecanoic acid ethyl ester 2-(6,7,8 The ,9-tetrahydro-dibenzofuran-2-yloxy)-dodecanoic acid ethyl ester,

22

HP : 1.5133; .

of 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 3.35 g (10.0 mmol) 2-bromo-tetradecanoic acid ethyl ester 2-(6,7 ,8,9-: tetagahydro-dibenzofuran-2-yloxy)-tetradecanoic acid ethyl ester, r^ 0 : 1.5098;

of 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 3.63 g (10.0 mmol) 2-bromo-hexadecanoic acid ethyl ester 2-(6,7 The ,8,9-tetrahydro-dibenzofuran-2-yloxy)-hexadecanoic acid ethyl ester,

n£° : 1.5062}

of 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 2.35 g (10.0 mmol) cc-bromo-cyclopentaneacetic acid ethyl ester a-(6,7 ,8,9-tetrahydro-dibenzofuran-2-yloxy)-cyclopentaneacetic-

20

acid ethyl ester, n£J : 1.5423;

of 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 2.49 g (10.0 mmol) oc-bromo-cyclohexaneacetic acid ethyl ester a-(6,7 ,8,9-tetrahydro-dibenzofuran-2-yloxy)-cyclohexaneacetic acid ethyl ester, n£° : 1.5422;

of 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 1.95 g (10.0 mmol) 2-bromobutyric acid ethyl ester 2-(6,7 ,8,9-tetrahydro-dibenzofuran-2-yloxy)-butteric acid ethyl ester,

r£<u> 1.5372.

The 6,7,8,9-tetrahydrodibenzo-furan-2-ol used as starting material can be prepared in the following way: a) In a three-neck round flask with a thermometer, stirrers and reflux skirts, 36.7 g (0.25 mol) of the sodium salt of hydroquinone-monomethyl ether in portions to which was added a solution of 46.6 g (0.264 mol) of 2-bromo-cyclohexanone in 130 ml of abs. toluene, whereby the temperature rises from 25 - 50°. The yellow mass thus obtained is now heated for 2 hours under reflux, whereby the sodium salt of the hydroquinone monomethyl ether dissolves successively with the simultaneous precipitation of sodium bromide.

After cooling, this is taken up in 700 ml of ether and the ether-containing solution is washed 4 times with a total of 200 ml of 15% potassium hydroxide and water, dried over magnesium sulphate and evaporated in vacuo. 2-(4-methoxy-phenoxy)-cyclohexanone is thus obtained as a yellow oil. After recrystallization twice in ether-hexane, the pure 2-(4-methoxy-phenoxy)-cyclohexanone is obtained in the form of pale yellow needles with m.p. 77 - 79°.

b) In a round flask with stirrers, add 4.0 g (18.0 mmol) of 2-(4-methoxy-phenoxy)-cyclohexanone in portions to 40 ml

phosphoric acid (d = 1.71), whereby a clear solution is obtained which is then heated for 2 1/2 hours at 105°. Thereby, the solution changes color from green to reddish brown, and at the same time an almost colorless oil is secreted. After cooling, the reaction mixture is poured into ice and extracted twice together

200 ml of ether. The ethereal solution is washed with 1-1 sodium hydroxide solution and water, dried over magnesium sulphate and evaporated in a vacuum. 2-Methoxy-6,7,8,9-tetrahydro-dibenzofuran is obtained as a brown oil, which is distilled twice in a coal furnace at 0.005 torr between 80 - 100°. The pure 2-methoxy-6,7,8,9-tetrahydro-dibenzofuran thus obtained is a colorless oil, n°: 1.5783. c) In a round bottom flask with reflux skirts and a potassium hydroxide drying rack, 3.0 g (14.85 mmol) of 2-methoxy-6,7,8,9-tetrahydro-dibenzofuran is heated for 2 3/4 hours with stirring at 20.0 g pyridine hydrochloride at 170°. The reaction mixture is then heated to a mixture of 200 g of ice and 100 ml of 1N hydrochloric acid and stirred for a further 1/2 hour.

The 6,7,8,9-tetrahydro-dibenzofuran-2-ol, which precipitates in white crystals, is filtered off and washed with water until the wash water becomes neutral. After drying in high vacuum, pure 6,7,8,9-tetrahydro-dibenzofuran-2-ol is obtained as a white powder with m.p. 106 - 107°.

EXAMPLE 2

3.76 g (20.0 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-3-ol are added to a round-bottom flask with reflux skirts, dropping funnel, potassium hydroxide drying tube, stirrer and gas introduction tube to a solution of 0.46 g (20.0 mmol) sodium in 80 ml abs. ethanol under a nitrogen atmosphere. To the thus obtained solution of sodium 6,7,8,9-tetrahydro-dibenzofuran-3-olate, 5.02 g (20.0 mmol) of 2-bromo-octanoic acid ethyl ester are added dropwise while stirring and refluxed for 3 hours . After cooling, the reaction mixture is evaporated in vacuo and the residue is distributed between water and ether. The ether phase is separated and evaporated, after washing with water to pH = 7 and drying with magnesium sulphate, in a vacuum, whereby a pale yellow oil is obtained.

The crude 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-octanoic acid ethyl ester, which is still contaminated with 6,7,8,9-tetrahydro-dibenzofuran-3-ol, is purified by column chromatography (neutral silica gel 0.05 - 0.2 mm Merck, solvent benzene). The benzene fractions containing the desired esters are combined

and evaporated. After drying in high vacuum, the pure 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-octanoic acid ethyl ester is obtained, a faint yellow pungent oil, nT : 1.5233.

Analogously, one obtains:

of 2.82 g (15.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 2.8 g (15.0 mmol) 2-bromo-propionic acid ethyl ester 2-(6,7 The ,8,9-tetrahydro-dibenzofuran-3-yloxy)-propionic acid ethyl ester,

n£° : 1.5426;

of 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 1.95 g (10.0 mmol) 2-bromo-succinic acid ethyl ester 2-(6,7 The ,8,9-tetrahydro-dibenzofuran-3-yloxy)-butyric acid ethyl ester,

20

n£° : 1.5376;

of 2.82 g (15.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 2.92 g (15.0 mmol) 2-bromo-2-methyl-propionic acid ethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-2-methyl-propionic acid-20

ethyl ester, : 1.5366;

of 2.82 g (15.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 3.56 g 2-bromo-isoheptanoic acid ethyl ester 2-(6,7,8,9-tetrahydro -dibenzofuran-3-yloxy)-isoheptanoic acid ethyl ester, n^ : 1.5260;

of 3.76 g (20.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 6.14 g (20.0 mmol) 2-bromo-dodecanoic acid ethyl ester 2-(6,7 ,8,9-Tetrahydro-dibenzofuran-3-yloxy)-dodecanoic acid ethyl ester, n^° r 1.5155;

of 2.82 g (15.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 5.45 g (15.0 mmol) 2-bromo-hexadecanoic acid ethyl ester 2-(6,7 ,8,9-tetrahydro-dibenzofuran-3-yloxy)-hexadecanoic acid ethyl ester,

n£° in 1.5075;

of 3.76 g (20.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 4.99 g (20.0 mmol) oc-bromo-cyclohexaneacetic acid ethyl ester a-(6,7 ,8,9-tetrahydro-dibenzofuran-3-yloxy)-cyclohexaneacetic acid ethyl ester, 20 : 1.5445.

The starting product 6,7,8,9-tetrahydro-dibenzofuran-3-61 can be prepared in the following way: a) In a three-necked round flask with a thermometer, stirrers and reflux skirts, 300.0 g (2.05 mol) of the sodium salt of the resorcin monomethyl ether in portions added to a solution of 382.0 g (2.16 mol) of 2-bromo-cyclohexanone in 825 mol of abs. toluene, whereby the temperature rises from 25° to 60°. The yellow groat thus obtained is then heated for 2 hours under reflux, whereby the sodium salt of the resorcin monomethyl ether is successively dissolved with simultaneous precipitation of sodium bromide. After cooling, the reaction mixture is partitioned between ether

and water, separates the ether phase and washes this four times with a total of 2.0 1 15% potash and water, dries it over magnesium sulphate and evaporates it in a vacuum. The crude 2-(3-methoxy-phenoxy)-cyclohexanone is thus obtained as a yellow oil. After recrystallization twice in ether-hexane, the pure 2-(3-methoxy-phenoxy)-cyclohexanone is obtained in the form of pale yellow crystals with m.p. 72.5 - 73°. The non-crystallizing mother liquor can also be further processed accordingly

b).

b) In a round-bottomed flask with stirrers, 134.0 g (0.61 mol) of 2-(3-methoxy-phenoxy)-cyclohexanone are added in portions to 1340 ml of phosphoric acid (d = 1.71), whereby a green solution which is finally heated for 2 hours to 105°. After cooling, the reaction mixture is poured into ice and extracted with ether. The ethereal solution is washed with 1-1 sodium hydroxide solution and water, dried over magnesium sulphate and evaporated in a vacuum.

A mixture of 3- and 1-methoxy-6,7,8,9-tetrahydro-dibenzofuran is obtained in the form of a brown oil, which is distilled below 0.005 torr between 99 - 108°. In this way, a colorless oil is obtained, which, according to the NMR spectrum, contains approx. 8% 1-methoxy-6,7,8,9-tetrahydro-dibenzofuran, and which without further purification is further processed.

c) In a round-bottomed flask with reflux skirts and potassium hydroxide drying tubes, 129.1 g (0.64 mol) of a according to b) are obtained

mixture of 3- and 1-methoxy-6,7,8,9-tetrahydro-dibenzofuran heated for 2 3/4 hours with stirring with 401.1 g of pyridine hydrochloride to 170°. The still warm reaction mixture is then completely mixed with 800 g of ice and 400 ml of 1-n hydrochloric acid and stirred for a further 1/2 hour. The precipitated oil is extracted with ether and the ether-containing solution is evaporated, whereupon on cooling the crude 6,7,8,9-tetrahydro-dibenzofuran-3rr ol crystallizes out. Extraction is carried out and crystallized twice more in ether-petrol. The pure 6,7,8,9-tetrahydro-dibenzofuran-3-ol is thus obtained in the form of pale yellow crystals with m.p. 105 - 106°, while 6,7,8,9-tetrahydro-dibenzofuran-1-ol remains in the mother liquor.

EXAMPLE 3

In a round-bottomed flask equipped with a reflux condenser, a trip funnel, a potassium hydroxide separator, stirrers and a gas introduction tube, add

add 1.0 g (4.9 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-thiol to a solution of 0.112 g (4.9 mmol) sodium in 10 ml abs.

ethanol under a nitrogen atmosphere.

To the thus obtained solution of sodium 6,7,8,9-tetrahydro-dibenzofuran-2-thiol, 1.23 g (4.9 mmol) of 2-bromo-octanoic acid ethyl ester are added dropwise while stirring and boiled* for 3 hours under reflux, whereby nitrogen is continuously passed through the solution. After cooling, the reaction mixture is evaporated in vacuo and the residue is distributed between water and ether. After washing with water to pH = 7 and drying with magnesium sulfate, the ether solution is evaporated, whereby a yellow oil is obtained. The crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-octanoic acid ethyl ester, which is still contaminated with 6,7,8,9-tetrahydro-dibenzofuran-2-thiol, is purified by using column chromatography (neutral silica gel 0.05 - 0.2 mm, Merck, solvent benzene). The benzene fractions containing the desired ester are combined and evaporated. After drying in high vacuum, the pure 2-(6,7,8,9-tetrahydro-dibenzo-furan-2-ylthio)-octanoic acid ethyl ester is obtained, a colorless oil,

20 , c.,c

n^ : 1.5465.

Analogously, one obtains:

of 1.43 g (7.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-thiol and 1.27 g (7.0 mmol) 2-bromo-propionic acid ethyl ester 2-(6,7 ,8,9-tetrahydro-dibenzofuran-2-ylthio)-propionic acid ethyl ester,

20

n£° : 1.5699;

of 2.0 g (9.78 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-thiol and 1.92 g (9.78 mmol) 2-bromo-2-methyl-propionic acid ethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-2-methyl-propionic acid-20

ethyl ester, n£ : 1, 5663;

of 1.43 g (7.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-thiol and 1.66 g (7.0 mmol) 2-bromo-isoheptanoic acid ethyl ester 2-(6,7 ,8,9-tetrahydro-dibenzofuran-2-ylthio)-isoheptanoic acid ethyl ester,

n£° : 1.5503;

of 0.7 g (3.42 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-thiol and 1.24 g (3.42 mmol) 2-bromo-hexadecanoic acid ethyl ester 2-(6,7 ,8,9-tetrahydro-dibenzofuran-2-ylthio)-hexadecanoic acid ethyl ester, in 1.5245.

The 6,7,8,9-tetrahydro-dibenzo-furan-2-thiol used as starting material can be prepared as follows: a) In a round flask with reflux skirts, stirrers, potassium hydroxide drying tube, thermometer and gas introduction tube, add in small portions 0, 48 g (10.0 mmol) of 50% sodium hydride dispersion to a solution of 1.88 g (10.0 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-2-ol in 10 ml of dimethylformamide under a nitrogen atmosphere . After 1/2 hour, hydrogen evolution has stopped. The obtained dark brown suspension is now cooled to 10 and then 1.65 g (13.0 mmol) of dimethylthiocarbamic acid chloride is added all at once. Thereby the temperature instantly rises to 18°. The whole is then heated for another hour to 80°, whereby sodium chloride precipitates out in the now light brown colored solution. After cooling, it is evaporated in a vacuum and the remaining brown oil is distributed between ether and water. The ether phase is washed several times with cold diluted caustic soda and water, dried over magnesium sulfate and evaporated, leaving the crude dimethylthiocarbamic acid O-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-ester as a yellow-brown oil. This is purified by means of column chromatography [silica gel 0.05 - 0.2 mm, Merck, solvent benzene-acetic ester X?:1)]. After evaporation of the pure fraction, this is recrystallized twice in aqueous methanol with the addition of activated carbon. The pure dimethylthiocarbamic acid O-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-ester is thus obtained with m.p. 129 - 131°. b) In a round flask equipped with magnetic stirrers and a gas inlet stirrer, 9.6 g (35 mmol) of dimethylthiocarbamic acid O-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-ester were heated for 3 1/2 hours at 280 - 295° under a nitrogen atmosphere and with stirring. The dark brown oil thus obtained can be further processed directly according to c). If desired, it is purified using a column chromatograph in [silica gel 0.05 - 0.2 mm, Merck, solvent benzene-acetic ester (9:1)]j. The pure fractions are combined and evaporated. After recrystallization twice in aqueous methanol, the pure dimethylthiocarbamic acid S-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-ester is obtained with m.p. 73 - 74°. c) In a round bottom flask with reflux skirts, stirrers, potassium hydroxide drying tube and gas introduction tube, a solution of

3.0 g (11.0 mmol) dimethylthiocarbamic acid S-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-ester (crude product) in 18.8 ml of 10% caustic soda and 60 ml methanol boiled 3 1/2 hours under a nitrogen atmosphere and with reflux. After cooling, the methanol is evaporated in vacuo, the residue acidified with 2-n hydrochloric acid and extracted with ether. After washing the ethereal solution with more water

pH = 7 and drying over magnesium sulphate, evaporation is carried out again. The crude 6,7,8,9-tetrahydro-dibenzo-furan-2-thyl is obtained as a yellow oil, which is purified by means of column chromatography [silica gel 0.05 - 0.2 mm, Merck, solvent benzene-acetic ester (9 :1)]. The pure fractions are combined and evaporated. After recrystallization in aqueous ethanol, 6,7,8,9-tetrahydro-dibenzofuran-2-thiol is obtained in the form of pale yellow crystals with m.p. 44.5 - 46°.

EXAMPLE 4

4.08 g (20 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-3-thiol is added to a solution of 0.46 g (20 mmol) sodium in 100 ml abs.

ethanol under a nitrogen atmosphere»

To the thus obtained solution of sodium 6,7,8,9-tetrahydro-dibenzofuran-3-thiolate, 5.02 g (20 mmol) of 2-bromo-octanoic acid ethyl ester is added dropwise while stirring and refluxed for 3 hours, whereby nitrogen is continuously passed through the solution. After cooling, the reaction mixture is evaporated under vacuum and the residue is distributed between water and ether. After washing with water to pH = 7 and drying with magnesium sulphate, the ether solution is evaporated. The obtained crude (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-octanoic acid ethyl ester, which still

is contaminated with 6,7,8,9-tetrahydro-dibenzofuran-3-thiol,

is purified by means of column chromatography (neutral silica gel 0.05 - 0.2 mm, Merck, solvent benzene). The benzene fractions, which contain the desired ester, are purified and evaporated. After drying in high vacuum, the pure 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-octanoic acid ethyl ester is obtained,

20°

a yellow oil with a pungent odor, : 1.5517.

Analogously, one obtains:

of 2.04 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 1.81 g (10.0 mmol) 2-bromo-propionic acid ethyl ester 2-(6,7 ,8,9-tetrahydro-dibenzofuran-3-ylthio)-propionic acid ethyl ester,

n£° : 1.57685 '

of 3.06 g (15 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 4.6 g (15 mmol) 2-bromo-dodecanoic acid ethyl ester 2-(6,7,8,9 -tetrahydro-dibenzofuran-3-ylthio)-dodecanoic acid ethyl ester,

20

n<£u>: 1.5392;

of 1.7 g (8.35 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 3.03 g (8.35 mmol) 2-bromo-hexadecanoic acid ethyl ester 2-(6,7 ,8,9-tetrahydro-dibenzofuran-3-ylthio)-hexadecanoic acid ethyl ester,

n£° : 1.5296;

of 2.04 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 1.95 g (10.0 mmol) 2-bromo-2-methyl-propionic acid ethyl ester 2- The (6,7,-8,9-tetrahydro-dibenzofuran-3-ylthio)-2-methyl-propionic acid ethyl ester.

The 6,7,8,9-tetrahydro-dibenzo-furan-3-thiol used as starting material can be prepared as follows:

a) Analogous to example 3 a) one obtains

of 22.6 g (0.12 mol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and

19.8 g (0.16 mol) dimethylthiocarbamic acid chloride dimethylthiocarbamic acid O-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ester, m.p. 158 - 159° (in vinegar).

b) Analogous to example 3b), one obtains

of 19.0 g (69.0 mmol) dimethylthiocarbamic acid-O-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ester dimethylthiocarbamic acid-S-(6,7,8,9-tetrahydro-dibenzofuran -3-yl)-ester, m.p. 102 - 103° (in ethanol-water).

c) Analogous to example 3 c) one obtains

of 11.75 g (42.0 mmol) dimethylthiocarbamic acid S-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ester 6,7,8,9-tetrahydro-dibenzofuran-3-thiol, m.p. 73 - 74° (in methanol-water).

EXAMPLE 5

To a solution of 0.23 g (10.0 mmol) of sodium in 23 ml of abs. of ethanol, 2.043 g (10.0 mmol) of 6,7,8,9-tetrahydro-dibenzothiophen-2-ol are added. Under the introduction of nitrogen, 2.51 g (10.0 mmol) of 2-bromo-octanoic acid ethyl ester are added dropwise to the solution and the reaction mixture is heated under reflux for 2 hours. After cooling, the ethanol is distilled off in a vacuum, and the residue is distributed between water and ether. The ether extract, which

is washed neutrally with water, washed over sodium sulphate and evaporated in a vacuum. The crude product is purified using column chromatography and silica gel 0.05 - 0.2 mm, Merck, elution with benzene. 2-(6,7,8,9-tetrahydro-dibenzothiophene-2-yloxy)-octanoic acid ethyl ester is obtained in the form of a colorless oil, n^ 20 : 1.5498. [With benzene-acetic ester (9:1) some starting phenol is still eluted].

Analogously, one obtains:

of 1.40 g (6.85 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-2-ol and 2.12 g (6.85 mmol) 2-bromo-dodecanoic acid ethyl ester 2-(6,7,8 ,9-tetrahydro-dibenzothiophene-(2-yloxy)-dodecanoic acid ethyl ester,

n£° 1.53235

of 2.50 g (12.24 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-2-ol and 4.45 g (12.2 mmol) 2-bromo-hexadecanoic acid ethyl ester 2-(6,7 ,8,9-tetrahydro-dibenzothiophen-2-yloxy)-hexadecanoic acid ethyl ester, n£° : 1.5271;

jav 2.5o g (12.24 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-2-ol and i 2.21 g (12.2 mmol) 2-bromo-propionic acid ethyl ester 2-(6, 7,8,9-: tetrahydro-dibenzothiophen-2-yloxy)-propionic acid ethyl ester, m.p. ' 71 - 72° (in hexane)5

of 2.50 g (12.24 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-2-ol and 2.38 g (12.2 mmol) 2-bromo-2-methyl-propionic acid ethyl ester 2-(6 ,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-2-methyl-propionic acid ethyl ester, m.p. 62 - 63.5° (in hexane)5

of 2.50 g (12.24 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-2-ol and 2.56 g (12.2 mmol) 2-bromo-3-methyl-butyric acid ethyl ester 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-3-methylbutyric acid ethyl ester, m.p. 59 - 60° (in hexane).

The 6,7,8,9-tetrahydro-dibenzothiophen-2-ol used as starting material can be prepared as follows: a) 12 g (50.78 mmol) of 2-(p-methoxy-phenylthio)-cyclohexanone are added while stirring and introduction of nitrogen to 120 ml oz. phosphoric acid (d = 1.71). The reaction mixture is heated to 85° and stirred at this temperature for 14 hours. After cooling at room temperature, it is poured onto ice and extracted with ether. The combined ether phases are washed with 2N caustic soda and water, dried over sodium and evaporated in vacuo. The purification of the crystalline precipitated crude product takes place by column chromatography on silica gel 0.05 - 0.2 mm, Merck, eluent benzene-hexane [3:2%].

Pure 2-methoxy-6,7,8,9-tetrahydro-dibenzothiophene is thus obtained, m.p. 85° (in hexane). b) 3.5 g (16.03 mmol) of 2-methoxy-6,7,8,9-tetrahydro-dibenzothiophene is added to 28 g (0.24 mol) of melted pyridine hydrochloride. The reaction mixture, which is in a nitrogen atmosphere, is stirred for 2 hours at 160 - 165° and, after cooling, is distributed between 2-n hydrochloric acid and ether. The combined ether extracts are washed neutrally with water, dried over sodium sulphate and evaporated in vacuo. The crystalline precipitated crude product is purified by column chromatography on silica gel 0.02 - 0.5 mm, Merck.

[Elution with benzene and benzene-acetic ester (9:1)]. The fractions containing the desired product are evaporated and recrystallized in methylene chloride-hexane. The 6,7,8,9-tetrahydro-dibenzothiophen-2-ol obtained melts at 113 - 114°.

EXAMPLE 6

Analogous to example 5, one obtains:

of 4.08 g (20.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-3-ol and 5.02 g (20.0 mmol) 2-bromo-octanoic acid ethyl ester 2-(6,7 The ,8,9-tetrahydro-dibenzothiophen-3-yloxy)-octanoic acid ethyl ester, -n£°: 1.5482; of 2.04 g (10.0 mmol) 6,7,8,9-tetrahydro-diben2thiophen-3-yl and 1.81 g (10.0 mmol) 2-bromo-propionic acid ethyl ester 2-(6,7 ,8,9-tetrahydro-dibenzothiophen-3-yloxy)-propionic acid ethyl ester, m.p. 41 - 43° (in hexane);

of 1.02 g (5.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-3-ol and 1.82 g (5.0 mmol) 2-bromo-hexadecanoic acid ethyl ester 2-(6,7 The ,8,9-tetrahydro-dibenzothiophen-3-yloxy)-hexadecanoic acid ethyl ester, m.p. 34 - 37° (in hexane);

of 2.04 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-3-yl and 1.95 g (10.0 mmol) 2-bromo-2-methyl-propionic acid ethyl ester 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-2-methyl-propionic acid ethyl ester;

The 6,7,8,9-tetrahydro-dibenzothiophen-3-ol used as starting material is prepared as follows: a) To a solution of 23.0 g (1.0 mol) sodium in 700 ml abs. ethanol is added while stirring and introduction of nitrogen

140.2 g (1.0 mol) of m-methoxythiophenol. Over the course of 15 minutes, 177.0 g (1.0 mol) of 2-bromo-cyclohexanone are then added dropwise, whereby the reaction mixture is heated. It is then boiled

another 1 1/2 hours during the return run. The ethanol is then evaporated in a vacuum and the residue is distributed between water and ether. The ether extract washed neutrally with water and dried over sodium sulfate is evaporated. For purification, the crude product is fractionated in high vacuum (20 cm Vigreux column). One obtains 2-(m-methoxy-phenylthio)-cyclohexanone with b.p. 146-147°/o.15 torr, in the form of a yellow-colored oil, r^: 1.5786;

b) 118.5 g (0.5 mol) of 2-[m-methoxy-phenylthio]-cyclohexanone are added while stirring and introduction of nitrogen to 1200 ml

concentrated phosphoric acid (d = 1.71). The reaction mixture is heated to 105° and stirred for 5 hours at this temperature.

After cooling to room temperature, it is poured over ice and

extracted with ether. The combined ether phases are washed with 2N caustic soda and water, dried over sodium sulfate and evaporated in vacuo. The crude product is purified by chromatography on silica gel [Merck, 0.05-0.2 mm, elution with benzene-hexane (1:3)].

3-Methoxy-6,7,8,9-tetrahydro-dibenzothiophene is obtained with

m.p. 46 - 46.5° (in methanol).

1-Methoxy-6,7,8,9-tetrahydro-dibenzothiophene is isolated as a by-product, m.p. 57-58° (in methanol).

c) 54.57 g (0.25 mol) 3-methoxy-6,7,8,9-tetrahydro-dibenzo-

thiophene is added while stirring and introduction of nitrogen to

a melt of 150 g (0.77 mol) of freshly distilled pyridine hydrochloride. The mixture is heated to 220 for 1.25 hours

and then introduce the melt into a mixture of 400 ml of 2-N hydrochloric acid and 200 g of ice. After extraction with ether-methylene chloride (3:1) and washing the organic phase with water,

drying over sodium sulfate and evaporation in vacuo the resulting crystalline crude product is filtered over silica gel [Merck,

0.05 - 0.2 mm, eluted with benzene-ethyl acetate (9:1)] and recrystallized in methylene chloride-hexane. 6,7,8,9-tetrahydro-dibenzo-thiophen-3-ol is obtained with m.p. 117 - 118° (in methanol).

EXAMPLE 7

To a solution of 0.11 g (4.78 mmol) of sodium in 20 ml of abs.

of ethanol, 1.0 g (4.54 mmol) of 6,7,8,9-tetrahydro-dibenzo-thiophene-2-thiol is added. Under agitation and introduction of

nitrogen is added dropwise to this solution quickly 0.86 g (4.78

mmol) 2-bromopropionic acid ethyl ester. The reaction mixture is boiled for 3 hours under reflux. After cooling, the ethanol is evaporated in a vacuum and the residue is distributed between water and ether. The ether extract, washed neutrally with water and dried over sodium sulfate, is evaporated in a vacuum and the remaining residue is purified,

yellow colored oil by column chromatography on silica gel, Merck, elution with benzene-hexane (2:1). 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-propionic acid ethyl ester is obtained in

■ 20

; form of a colorless oil, : 1.6023.

Analogously, one obtains:

of 1.40 g (6.36 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol : and 1.64 g (6.53 mmol) 2-bromo-octanoic acid ethyl ester 2-(6,7,8,9-

: tetrahydro-dibenzothiophen-2-ylthio)-octanoic acid ethyl ester,

• 4°: i»5728?

of 1.0 g (4.54 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol I and 1.47 g (4.80 mmol) 2-bromo-dodecanoic acid ethyl ester 2-(6, 7,8,9-

: tetrahydro-dibenzothiophen-2-ylthio)-dodecanoic acid ethyl ester, ; : 1.5561;

; of 1.0 g (4.54 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 1.73 g (4.78 mmol) 2-bromo-hexadecanoic acid ethyl ester 2-(6, 7,8,9-' tetrahydro-dibenzothiophen-2-ylthio)-hexadecanoic acid ethyl ester,

20°

In n^0 : 1.5439;

of 1.0 g (4.54 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 0.94 g (4.82 mmol) 2-bromo-2-methyl-propionic acid ethyl ester in 2 -(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-2-methyl-propion-

In acid ethyl ester.

The 6,7,8,9-tetrahydro-dibenzo-tLophen-2-thiol used as starting material can be prepared as follows: a) To the one at approx. 5° cooled the solution of 10.0 g (49.0 I mmol) of 6,7,8,9-tetrahydro-dibenzothiophen-2-ol in 50 ml of abs. 2.35 g (49.0 mmol) of 50% sodium hydride dispersion is added in portions to dimethylformamide while stirring and introduction of nitrogen. After 1/2 hour of stirring at room temperature and 5 minutes at 80°, hydrogen evolution is complete. Then, at 5 - 10°, 8.07 g (65.4 mmol) of dimethylthiourea-■ acid chloride are added dropwise in 10 ml abs. dimethylformamide in ]bpet of approx. 2 minutes and the reaction mixture is stirred for a further 2 hours at 80°. After

after cooling, it is evaporated in a vacuum, the residue is taken up in water and extracted thoroughly with ether and chloroform. The combined organic phases are washed with water, dried over magnesium sulphate, evaporated and the residue purified by column chromatography on silica gel 0.05 - 0.2 mm, Merck, elution with benzene-acetic acid

ester [9:1].

The dimethylthiocarbamic acid O-(6,7,8,9-tetrahydro-dibenzothiophen-2-yl) ester is obtained with m.p. 154 - 155° (methanol or acetic acid).

b) In a nitrogen atmosphere, 9.0 g (30.9 mmol) of dimethylthiocarbamic acid-O-(6,7,8,9-tetrahydro-dibenzothiophen-2-yl)-

ester at 250° until the melt and then heat 3 minutes at 350°. After cooling (using air flow)

the yellow residue is purified by column chromatography on silica gel, Merck [elution with benzene-acetic ester (19:1)]. The fractions containing the desired product are collected and recrystallized in methanol. Dimethylthiocarbamic acid S-(6,7,8,9-tetrahydro-dibenzothiophen-2-yl)-ester is thus obtained with m.p. 98 - 99° (in methanol). c) While stirring and introducing nitrogen, 5.1 g (17.5 mmol) of dimethylthiocarbamic acid S-(6,7,8,9-tetrahydro-dibenzothiophen-2-yl)-ester are boiled in 100 ml of methanol and 80 ml 10% caustic soda 3 hours under reflux. The organic solvent is then evaporated in vacuo, the residue acidified with 1-n hydrochloric acid and extracted with ether. The ether phase, washed with water and dried over magnesium sulfate, is evaporated in vacuo and the residue is chromatographed on silica gel, Merck, eluting with benzene and benzene-acetic ester (19:1). After recrystallization in methylene chloride-hexane, 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol is obtained with m.p. 64 - 65°.

EXAMPLE 8

Analogous to example 7, one obtains:

of 1.30 g (5.90 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-3-

to and 1.48 g (5.90 mmol) 2-bromo-octanoic acid ethyl ester 2-(6,7,8,9-

tetrahydro-dibenzothiophen-3-ylthio)-octanoic acid ethyl ester,

n£° : 1.5754;

of 2.20 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-3-

thiol and 3.07 g (10.0 mmol) 2-bromo-dodecanoic acid ethyl ester 3.70 g 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio)-dodecane-20

acid ethyl ester, n^ : 1.5594;

of 2.20 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-3-thiol and 1.81 g (10.0 mmol) 2-bromo-propionic acid ethyl ester 2-(6,7 ,8,9-tetrahydro-dibenzothiophen-3-ylthio)-propionic acid ethyl ester;

of 2.20 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-3-thiol and 1.95 g (10.0 mmol) 2-bromo-2-methyl-propionic acid ethyl ester 2( 6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio)-2-methyl-propionic acid ethyl ester.

The 6,7,8,9-tetrahydro-dibenzo-tLophen-3-thiol used as starting material can be prepared analogously to that in example 7 a), b)

and c) described reaction sequence:

a) Analogous to example 7 a), 16.0 g (78.3 mmol) of 6,7,8,9-tetrahydro-dibenzothiophen-3-ol and 12.95 g (104.9 mmol) are obtained

Dimethylthiocarbamic acid chloride The dimethylthiocarbamic acid O-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-ester with m.p. 139.5 - 140 (in methanol).

b) Analogous to example 7b), but at a reaction temperature of 260° and a reaction duration of 5 hours, 12.10 g is obtained

(41.5 mmol) dimethylthiocarbamic acid-O-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-ester dimethylthiocarbamic acid-S-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl) )-ester with m.p. 98 - 99°

(in methanol).

c) Analogous to example 7 c), 8.74 g (30.0 mmol) of dimethylthiocarbamic acid S-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-ester 6,7,8,9 is obtained -tetrahydro-dibenzothiophene-3-thiol with m.p. 36 - 36.5° (in hexane).

EXAMPLE 9

2.82 g (15 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-2-ol are added to a solution of 0.345 g (15 mmol) in a round-bottomed flask with reflux skirts, dropping funnel, potassium hydroxide drying tube, stirrers and gas introduction tube sodium in 25 ml abs. ethanol under a nitrogen atmosphere. To the thus obtained solution of sodium 6,7,8,9-tetrahydro-dibenzofuran-2-olate, a similarly prepared ethanolic solution of the sodium salt of 2-bromoheptanoic acid [of 3.14 g (15 mmol) 2-bromoheptanoic acid, 0.345 g (15 mmol) sodium, 60 ml abs. ethanol] and boil for 8 hours under.reverse. After cooling, the reaction mixture is evaporated in vacuo, the remaining residue is suspended in water and acidified with conc. hydrochloric acid. The thus precipitated oil is taken up in ether. The ethereal solution is washed with water, dried with magnesium sulfate and the solvent is evaporated in vacuo. The crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid, remaining as an oil,

which is still mainly contaminated with 6,7,8,9-tetrahydro-dibenzofuran-2-ol, is purified by column chromatography on silica gel 0.05-0.2 mm, Merck, solvent benzene-glacial acetic acid (85:15). It. After evaporation of the pure fractions, the solid residue obtained is recrystallized twice in methanol-water. The pure 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid is thus obtained with m.p. 123 - 124°.

Analogously, one obtains:

of 2.82 g (15 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 2.30 g (15 mmol) 2-bromo-propionic acid 2-(6,7,8,9-tetrahydro -dibenzofuran-2-yloxy)-propionic acid with m.p. 128 - 129°

(in methanol-water);

of 2.82 g (15 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 3.34 g (15 mmol) 2-bromo-octanoic acid 2-(6,7,8,9-tetrahydro -

o dibenzofuran-2-yloxy)-octanoic acid with m.p. 99 - 100 (in methanol-water); ,

of 2.82 g (15 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 4.19 g (15 mmol) 2-bromo-dodecanoic acid 2-(6,7,8,9-tetrahydro -

dibenzofuran-2-yloxy)-dodecanoic acid with m.p. 65 - 66° (in pentane)5

of 2.82 g (15 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 3.35 g (15 mmol) 2-bromo-octanoic acid 2-(6,7,8,9-tetrahydro -dibenzofuran-3-yloxy)-octanoic acid with m.p. 78 - 79° (in hexane)5

of 2.82 g (15 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 4.19 g (15 mmol) 2-bromo-dodecanoic acid 2-(6,7,8,9-tetrahydro -dibenzofuran-3-yloxy) -dodecanoic acid with m.p. 87 - 87.5° (in hexane);

of 3.06 g (15 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-thiol and 3.35 g (15 mmol) 2-bromo-octanoic acid 2-(6,7,8,9-tetrahydro -dibenzofuran-2-ylthio)-octanoic acid with m.p. 86.5 - 88° (in hexane).

of 6.12 g (30 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 6.69 g (30 mmol) 2-bromo-octanoic acid 2-(6,7,8,9-tetrahydro -dibenzofuran-3-ylthio)-octanoic acid with m.p. 62 - 63° (in hexane);

of 6.12 g (30 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 8.37 g (30 mmol) 2-bromo-dodecanoic acid 2-(6,7,8,9-tetrahydro -dibenzofuran-3-ylthio)-dodecanoic acid with m.p. 73.5 - 74.5° (in hexane);

EXAMPLE IO

To a solution of 2.3 g (100 mmol) sodium in 100 ml abs. of ethanol, 10.20 g (50 mmol) of 6,7,8,9-tetrahydro-dibenzothiophen-2-ol are added. While stirring and introducing nitrogen, a solution of 11.15 g (50 mmol) of 2-bromo-octanoic acid in 60 ml of abs. ethanol quickly. The reaction mixture is boiled for 4 hours under reflux, then evaporated in vacuo and the residue taken up in water. After acidification with conc. hydrochloric acid is extracted with ether. The extract, washed neutrally with water and dried over sodium, is evaporated in vacuo and the remaining, yellow-trapped oil is purified by column chromatography on silica gel 0.05-0.2 mm, Merck, elution with benzene-acetic ester (9:1) and benzene-glacial acetic acid (19:1). After recrystallization of

the pure fractions in hexane yield 2-(6,7,8,9-tetra-

hydro-dibenzothiophen-2-yloxy)-octanoic acid with m.p. 90 - 91°.

Analogously, one obtains:

of 10.20 g (50 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-3-ol and 11.15 g (50 mmol) 2-bromo-octanoic acid 2-(6,7,8,9-tetrahydro -dibenzothiophene-3-yloxy)-octanoic acid with m.p. 106 -107° (in hexane)5

of 11.0 g (50 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 10.45 g.50 mmol 2-bromo-heptanoic acid 2-(6,7,8,9-tetrahydro-dibenzothioph en-2-ylthio)-heptanoic acid with m.p. 101° (in hexane);

of 11.0 g (50 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 11.15 g (50 mmol) 2-bromo-octanoic acid 2-(6,7,8,9-tetrahydro -dibenzothiophene-2-ylthio)-octanoic acid with m.p. 91 - 92° (in hexane);

of 11.0 g (50 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-3-thiol and 11.15 g (50 mmol) 2-bromo-octanoic acid 2-i6,7,8,9-tetrahydro- dxbenzothiophen-3-ylthio)-octanoic acid, n^ 20 : 1.5848, after purification by chromatography on silica gel, Merck 0.05-0.2 mm eluting with benzene and benzene-glacial acetic acid (49:1).

EXAMPLE 11

4.0 g (21 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-2-ol are added to a solution of 0.48 g (21 mmol) sodium in 50 ml abs. ethanol under a nitrogen atmosphere. To the thus obtained solution of sodium 6,7,8,9-tetrahydro-dibenzofuran-2-olate, a solution of 3.43 g (21 mmol) of 2-chloroheptanamide in 50 ml of abs. ethanol and boil for 6 hours under reflux. After cooling, the reaction mixture is evaporated in a vacuum and the residue is distributed between water and ether. After washing with water to pH = 7 and drying with magnesium sulfate, the ether solution is evaporated in vacuo and the residue crystallized twice in ethanol. Pure 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanamide is thus obtained with m.p. 145 - 146°.

Analogously, one obtains: from 4.0 g (21 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and ; 3.72 (21 mmol) 2-chloro-octanamide 2-(6,7,8,9-tetrahydro-dibenzo-furan-2-yloxy)-octanamide with m.p. 130 - 131° (in ethanol-water);j

of 4.0 g (21 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 2.25 g (21 mmol) 2-chloro-propionamide 2-(6,7,8,9-tetrahydro -dibenzofuran-2-yloxy)-propionamide;

of 4.0 g (21 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 4.90 g (21 mmol) 2-chloro-dodecanamide 2-(6,7,8,9-tetrahydro -dibenzofur an- 2-yloxy )-do decanamide with m.p. 112 - 112.5°;

(in ethanol);

of 4.0 g (21 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 3.72 g (21 mmol) 2-chloro-octanamide 2-(6,7,8,9-tetrahydro -dibenzofuran-3-yloxy)-octanamide with m.p. 140 - 141° (in ethanol)5

of 4.0 g (21 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 4.90 g (21 mmol) 2-chloro-dodecanamide 2-(6,7,8,9-tetrahydro -dibenzofuran-3-yloxy)-dodecanamide with m.p. 131.5 - 132.5°

(in vinegar)5

of 4.34 g (21 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-thiol and 3.72 g (21 mmol) 2-chloro-octanamide 2-(6,7,8,9-tetrahydro -dibenzofuran-2-ylthio)-octanamide with m.p. 135 - 136° (in ethanol)5

of 4.34 g (21 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 3.72 g (21 mmol) 2-chloro-octanamide 2-(6,7,8,9-tetrahydro -dibenzofuran-3-ylthio)-octanamide with m.p. 107.5 - 109°

(in ethanol-water)5

of 4.34 g (21 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-2-ol and 3.72 g (21 mmol) 2-chloro-octanamide 2-(6,7,8,9-tetrahydro -dibenzothiophene-2-yloxy)-octanamide with m.p. 142 - 143° (in ; acetone-hexane)5

of 4.34 g (21 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-3-ol and 3.72 g (21 mmol) 2-chloro-octanamide 2-(6,7,8,9-tetrahydro -dibenzothiophene-3-yloxy)-octanamide with m.p. 116 - 117° (in methanol)5

of 4.68 g (21 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 3.43 g (21 mmol) 2-chloro-heptanamide 2-(6,7,8,9-tetrahydro -dibenzothiophen-2-ylthio)-heptanamide with m.p. 150 - 150.5°

(in methanol)5

of 4.68 g (21 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-3-thiol and 3.72 g (21 mmol) 2-chloro-octanamide 2-(6,7,8,9-tetrahydro -dibenzothiophene-3-ylthio-octanamide.

EXAMPLE 12

In a round-bottomed flask with reflux skirts, 6.2 g (18 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid ethyl ester are boiled in a solution of 2.02 g (36 mmol) of potassium hydroxide of 60 ml of methanol and 6 ml of water for 4 hours under reflux.

After cooling, the reaction mixture is evaporated in vacuo, the residue is partitioned between dilute hydrochloric acid and ether. and ethers out. The combined ether solutions are washed neutrally with water, dried over magnesium sulphate and evaporated again. The crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid is obtained as a colorless oil. Pure 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid crystallizes from aqueous methanol with m.p. 123 - 124°.

Analogously and with the same quality, 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid is obtained from 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid -methyl- or

-propyl ester.

Analogously, one obtains:

of 4.6 g (16 mmol) 2-(6,7.,8,9-tetrahydro-dibenzofuran-2-yloxy)-propionic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-2- yloxy)-propionic acid, m.p. 128 - 129° (in methanol-water)5 of 1.25 g (4 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)- 2-methyl-propionic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzo-

'furan-2-yloxy)-2-methyl-propionic acid, m.p. 136.5 - 138° (in methanol-water);

of 4.0 g (13 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-pentanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) )-pentanoic acid, m.p. 98 - 100° (in pentane);

of 3.0 g (9 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-isoheptanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) )-isoheptanoic acid, m.p. 66 - 69° (in hexane);

of 11.6 g (35 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) )-octanoic acid, m.p. 99 - 100° (in hexane);

of 2.3 g (6 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-decanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy )-decanoic acid, m.p. 70 - 71° (in hexane);

of 4.0 g (10 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-dodecanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) )-dodecanoic acid, m.p. 65 - 66° (in pentane);

of 2.5 g (6 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-tetradecanoic acid ethyl ester 2-{6,7,8,9-tetrahydrodibenzofuran-2-yloxy)- tetradecanoic acid, m.p. 52.5 - 55° (in hexane);

of 2.8 g (6 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-hexadecanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) )-hexadecanoic acid, m.p. 55 - 56 (in hexane);

of 1.0 g (3 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-cyclopentaneacetic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzo-furan-2 -yloxy)-cyclopentaneacetic acid, m.p. 103 - 104° (in hexane);

of 1.7 g (5 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-cyclohexaneacetic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-2- yloxy)-cyclohexaneacetic acid, m.p. 133 - 134°

(in methanol-water)5

of 1.51 g (5 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-butyric acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) )-butyric acid, m.p. 95.5 - 97°.

EXAMPLE 13

In a round-bottomed flask with reflux skirts, 5.7 g (16 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-octanoic acid ethyl ester are boiled in a solution of 2.0 g (35 mmol) of potassium hydroxide in 50 ml of methanol and 5 ml of water for 3 hours under reflux. After cooling, the reaction mixture is evaporated in vacuo, the residue is distributed between dilute hydrochloric acid and ether, and the ethers are removed. The combined ether solutions are washed neutrally with water, dried over magnesium sulfate and evaporated again, the crude 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-octanoic acid remaining as a yellow oil . After crystallization twice in hexane, pure 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-octanoic acid is obtained in the form of pale yellow crystals with m.p. 78 - 79°.

Analogously, one obtains:

of 3.1 g (10.7 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-propionic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-3 - yloxy)-propionic acid, m.p. 144° (in benzene-hexane);

of 2.1 g (7 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-butyric acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) )-butyric acid, m.p. 106 - 107° (in hexane)5

of 2.4 g (8 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-2-methyl-propionic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzo -furan-3-yloxy)-2-methyl-propionic acid, m.p. 78 - 80° (in hexane);

of 3.9 g (11.3 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-isoheptanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzo-

furan-3-yloxy)-isoheptanoic acid, m.p. 104 - 105° (in hexane);

of 6.0 g (14.5 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-dodecanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-3 -yloxy)-dodecanoic acid, m.p. 87 - 87.5° (in hexane);

of 5.6 g (12.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-hexadecanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzo-furan -3-yloxy)-hexadecanoic acid, m.p. 77.5 - 78.5° (in methanol-water);

of 2.8 g (7.8 mmol) α-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-cyclohexaneacetic acid ethyl ester α-(6,7,8,9-tetrahydro-dibenzofuran- 3-yloxy)-cyclohexaneacetic acid, m.p. 118 - 120°

(in hexane).

EXAMPLE 14

In a round-bottomed flask with reflux skirts, 1.4 g (3.73 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-octanoic acid ethyl ester are boiled in a solution of 0.414 g (7.4 mmol ) potassium hydroxide in 20 ml of methanol and 1 ml of water for 5 1/2 hours under reflux. After cooling, the reaction mixture is evaporated in vacuum,

divide the residue between water and ether, acidify the aqueous phase with 2-N hydrochloric acid and etherify it. The combined ether solutions are washed neutrally with water, dried over magnesium sulphate and evaporated again. Crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-octanoic acid is obtained as a colorless oil. In hexane, the pure 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-octanoic acid crystallizes in the form of white crystals with m.p. 92 - 93°.

Analogously, one obtains:

of 1.6 g (5.2 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-propionic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-2 -ylthio)-propionic acid, m.p. 95° (in hexane);

of 2.7 g (8.47 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-2-methyl-propionic acid ethyl ester 2-(6,7,8,9-tetrahydro -dibenZofUran-2-ylthio)-2-methyl-propionic acid, m.p. 146 - 147A ge/ 0 (in ether-hexane);

of 2.1 g (5.8 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-isoheptanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-2 -ylthio)-isoheptanoic acid, mp 71.5 - 73° (in hexane);

of 0.8 g (1.645 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-hexadecanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio) )-hexadecanoic acid, m.p. 72 - 74 (in pentane).

EXAMPLE 15

In a round-bottomed flask with reflux skirts, 6.35 g (17 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-octanoic acid ethyl ester are boiled in a solution of 2.6 g (46 mmol) of potassium hydroxide in 60 ml of methanol and 6 ml of water for 4 hours under reflux. After cooling, the reaction mixture is evaporated in vacuo, the oily residue is suspended in water, acidified with dilute hydrochloric acid and etherified several times. The ether extracts are washed neutrally with water, dried over magnesium sulphate and evaporated again. Crystallization of the oily residue in hexane yields 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-octanoic acid in the form of white crystals with m.p. 62 - 63°.

Analogously, one obtains:

of 2.1 g (6.9 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-propionic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-3 -ylthio)-propionic acid, m.p. 133 - 134° (in methanol-water);

of 5.45 g (12.7 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-dodecanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-3 - ylthio)-dodecanoic acid, m.p. ;73.5 - 74.5° (in hexane);

of 3.6 g (7.4 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-hexadecanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-3 -ylthio)-hexadecanoic acid, m.p. 69 - 70° (in methanol).

EXAMPLE 16

A solution of 0.65 g ( 9.96 mmol) potassium hydroxide

(86%) in 5 ml of water. The mixture is boiled for 1 1/2 hours under reflux and evaporated in a vacuum. The remainder is distributed between dilute hydrochloric acid and ether. The ether phase washed neutrally with water is dried over sodium sulphate and evaporated in a vacuum. After recrystallization of the crude product in methylene chloride-hexane, 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-octanoic acid is obtained, m.p. 90 - 91°.

Analogously, one obtains:

of 1.92 g (4.46 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-dodecanoic acid ethyl ester 2-(6,7,8,9-tetrahydrodibenzothiophen-2-yloxy )-dodecanoic acid, m.p. 74 - 76° (in methylene chloride-hexane);

of 2.56 g (8.42 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-propionic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzothiophene- 2-yloxy)-propionic acid, m.p. 156 - 157° (in methylene chloride-hexane);

of 1.76 g (5.53 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-2-methyl-propionic acid ethyl ester 2-(6,7,8,9-tetrahydro -dibenzothiophene-2-yloxy)-2-methyl-propionic acid, m.p. 121 - 122°

(in methylene chloride-hexane);

of 1.80 g (5.42 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-3-methyl-butyric acid ethyl ester 2-(6,7,8,9-tetrahydro -dibenzothiophene-2-yloxy)-3-methylbutyric acid, m.p. 91 - 93° (in methylene chloride-hexane);

of 1.94 g (3.99 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophene-2-yloxy)-hexadecanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzothiophene -2-yloxy)-hexadecanoic acid, m.p. 89 -91° (in methanol).

EXAMPLE 17

Analogously to example 16, one obtains:

of 3.10 g (8.28 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-octanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzothiophen-3 - yloxy)-octanoic acid, m.p. 106 - 107° (hexane);

of 3.04 g (10.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-propionic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzothiophene- 3-yloxy)-propionic acid, m.p. 146 - 147° (hexane)5

of 2.43 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-hexadecanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzothiophene- 3-yloxy)-hexadecanoic acid, m.p. 71 - 72° (hexane).

EXAMPLE 18

Dissolve 1.0 g (3.12 mmol) of 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-propionic acid ethyl ester in 20 ml of methanol, add 0.75 g of potassium hydroxide and 2 ml of water and boil at the introduction of nitrogen for 1 1/2 hours under reflux. After cooling, the reaction mixture is evaporated in vacuo and the residue is distributed between dilute hydrochloric acid and ether. The ether phase is separated, washed neutrally with water, dried over sodium sulphate and evaporated. The thus precipitated crude acid is recrystallized in methylene chloride-hexane. 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-propionic acid is obtained, m.p. 106 - 107°.

Analogously, one obtains:

of 2.15 g (5.51 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-octanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzothiophen-2 -ylthio)-octanoic acid, m.p. 91 - 92° (hexane);

of 1.65 g (3.70 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-dodecanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzothiophene- 2-ylthio)-dodecanoic acid, m.p. 57 - 58° (in hexane);

of 1.92 g (3.83 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-hexadecanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzothiophene- 2-ylthio)-hexadecanoic acid with m.p. 68 - 70°

(hexane);

of 1.20 g (3.07 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio)-octanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzothiophen- 3-ylthio)-octanoic acid as an oil, n^ 20 : 1.5848;

of 3.20 g (7.17 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio)-dodecanoic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzothiophen-3 -ylthio)-dodecanoic acid seam oil, n^ 20 : 1.5718;

The purification of both of the latter, non-crystallizing acids can be done by chromatography on silica gel, Merck 0.05-0.2 mm by elution with benzene and benzene-glacial acetic acid (49:1).

EXAMPLE 19

Boil 3.15 g (10 mmol) of 2-(6j7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanamide in a round-bottomed flask with reflux skirts

in a solution of 3 g (50 mmol) of potassium hydroxide in 70 ml of ethanol and 7 ml of water for 20 hours under reflux. After cooling, the reaction mixture is acidified with 2-n hydrochloric acid, the ethanol is evaporated in vacuo, the remaining aqueous phase is etherified and the ether solution is washed twice with water. After drying with sodium sulphate, the ether phase is evaporated. The remaining, crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid is recrystallized twice in methanol-water,

m.p. for the pure acid is 123 - 124°.

Analogously, one obtains:

of 3.28 g (10 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanamide 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-

in octanoic acid with m.p. 99 - 100 (in hexane);

of 3.44 g of 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-octanamide in

2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-octanoic acid with m.p.

62 - 63° (in hexane).

EXAMPLE 20

Dissolve 160 g (4.60 mmol) of 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-'■.ylthio)-heptanamide in 40 ml of ethanol, add a solution of 2.3 g (41 mmol) of potassium hydroxide in 40 ml of water and the reaction-1 mixture is boiled for 45 hours under reflux. After evaporation of the ethanol in a vacuum, the residue is distributed between 1-1 hydrochloric acid and ; ether. The separated, washed with water and dried over sodium sulfate ether phase is evaporated and the crude product is recrystallized in

hexane. One thus obtains 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-heptanoic acid with m.p. 101°.

Analogously, one obtains:

of 1.38 g (4.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-octanamide 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) )-octanoic acid with m.p. 90 - 91° (in hexane)5

of .1.38 g (4.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-octanamide 2-(6,7,8,9-tetrahydro-dibenzothiophen-3- yloxy)-octanoic acid with m.p. 106 - lo7° (in hexane).

EXAMPLE 21

Boil 2.4 g in a round-bottomed flask with reflux condensers and stirrers

(7 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanamide in a mixture of 30 ml of 6-n hydrochloric acid and 50 ml of glacial acetic acid for 5 hours under reflux. After cooling, the reaction mixture is evaporated in vacuo and the remaining residue is taken up in ether. The ethereal solution is first washed with water, then extracted with 2N caustic soda, the alkaline extract is separated and washed with ether.

The alkaline solution is then acidified with conc. hydrochloric acid (pH=1) and the oil thus precipitated is taken up in ether. The ethereal solution thus obtained is washed neutrally with water, dried over magnesium sulfate and evaporated in vacuo, obtaining the crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid as a yellow oil. After recrystallization twice in hexane, the pure acid is obtained in the form of white crystals with m.p. 99 - 100°.

EXAMPLE 22

In a round-bottomed flask with reflux skirts, 0.3 g (1 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid nitrile is boiled in a solution of 0.3 g (5 mmol) of potassium hydroxide in 20 ml ethanol and 2 ml water 20 hours under reflux. After cooling, the reaction solution is acidified with 2-n hydrochloric acid, the ethanol is evaporated in vacuo, the remaining aqueous phase is etherified and the ether solution is washed twice with water. After drying with sodium sulphate, the ether phase is evaporated. The remaining,

The crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid is recrystallized in methanol-water, obtaining the pure acid with m.p. 123 - 124°.

Analogously, one obtains:

of 3.12 g (10 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid nitrile 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)- octanoic acid with m.p. 99 - 100° (in hexane);

of 3.12 g (10 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-octanoic nitrile 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)- octanoic acid with m.p. 78 - 79° (in hexane)5

of 3.28 g (10 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-octanoic nitrile 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)- octanoic acid with m.p. 86.5 - 88° (in hexane);

of 3.28 g (10 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-octanoic acid nitrile 2-(6,7,8,9-tetrahydrobenzofuran-3-ylthio)-octanoic acid with - m.p. 62 -.-63° (in hexane).

The 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid nitrile used as starting material can be prepared as follows: a) In a round flask with reflux skirts, dropping funnel, potassium hydroxide dryer, stirrers and gas inlet stirrer add

add 3.76 g (20 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-2-ol to a solution of 0.46 g (20 mmol) of sodium in 30 ml of abs. ethanol under a nitrogen atmosphere. To the thus obtained solution of sodium 6,7,8,9-tetrahydro-dibenzofuran-2-olate, 3.8 g (20 mmol) of 2-bromoheptanoic nitrile are added dropwise while stirring and refluxed for 2 hours. After cooling the reaction mixture is evaporated in a vacuum and the residue distributed between water and ether. After washing with water to pH=7 and drying with magnesium sulfate, the ether solution is evaporated, obtaining 6.0 g

of a brown oil.. The crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid nitrile, which is mainly still contaminated with 6,7,8,9-tetrahydro-dibenzofuran-2- etc., is purified by column chromatography (neutral silica gel 0.05 - 0.2 mm, Merck, solvent benzene). The benzene fractions containing the desired nitrile are combined and evaporated. After drying in high vacuum, the pure 2-(6,7,8,9-tetrahydro-dibenzo-furan-2-yloxy)-heptanoic acid nitrile is obtained, a yellow oil, n^ 20 : 1.5395.

Analogously, one obtains:

of 15.1 g (80 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 16.32 g (80 mmol) 2-bromo-octanoic nitrile 2-(6,7,8,9-tetrahydro -dibenzofuran-2-yloxy)-octanoic acid nitrile, 23 : 1.5355;

of 7.52 g (40 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 8.16 g (40 mmol) 2-bromo-octanoic nitrile 2-(6,7,8,9-tetrahydro -dibenzofuran-3-yloxy)-octanoic nitrile, <20> : 1.5366;

of 6.92 g (33.8 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-thiol and 6.9 g (33.8 mmol) 2-bromo-octanoic nitrile 2-(6,7,8 ,9-tetrahydro-dibenzofuran-2-ylthio)-octanoic nitrile, n^ 20: 1.5645;

of 4.08 g (20 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 4.1 g (20 mmol) 2-bromo-octanoic nitrile 2-(6,7,8,9-tetrahydro -dibenzofuran-3-ylthio)-octanoic acid nitrile, n^ 20 : 1.5704.

EXAMPLE 23

A solution of 5.0 g (89 mmol) of potassium hydroxide in 15 ml of water and boil the mixture for 24 hours under reflux. The ethanol is then evaporated in vacuo, the residue is acidified with 2-N hydrochloric acid and extracted with ether. The extract, washed neutrally with water and dried over sodium sulfate, is evaporated in a vacuum. The remaining, crude hydrolysis product is recrystallized in hexane. 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-octanoic acid with m.p. 90 - 91°.

of 3.28 g (10.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-octanoic nitrile 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) )-octanoic acid with m.p. 105 - 107° (in hexane);

of 3.30 g (10.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-heptanoic acid nitrile 2-(6,7,8,9-tetrahydro-dibenzo-thiophen-2 -ylthioheptanoic acid, mp 101 (in hexane);

of 3.44 g (0.010 mol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio)-octanoic nitrile 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio)- octanoic acid as an oil, n^ 20: 1.5848 after chromatographic purification on silica gel by elution with benzene and benzene-glacial acetic acid (49:1).

The 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-octanoic acid nitrile used as starting material can be prepared as follows: a) To a solution of 1.47 g (63.7 mmol) sodium in 120 ml abs. of ethanol, 13.0 g (63.7 mmol) of 6,7,8,9-tetrahydro-dibenzothiophen-2-ol are added. While stirring and introducing nitrogen, 13.0 g (63.7 mmol) of 2-bromooctanoic acid nitrile in 50 ml of abs. ethanol. The reaction mixture is boiled for 5 hours under reflux and then evaporated in vacuo. The residue taken up in water is extracted with ether. The ether phase is washed neutrally with water, dried over sodium sulphate and evaporated in vacuo. For purification, the crude product is chromatographed on silica gel, Merck 0.05-

0.2 mm, elution with benzene-hexane (2:1). 2-(6,7,8,9-tetrahydro-dibengothiophen-2-yloxy)-octanoic acid nitrile is obtained as a faint yellow oil, n^<0>: 1.5657.

Analogously, one obtains:

of 6.13 g (30.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-3-ol and 6.13 g (30.0 mmol) 2-bromo-octanoic nitrile 2-(6,7,8 ,9-tetrahydro-dibenzothiophen-2-yloxy)-octanoic nitrile, n£ 20: 1.5657;

of 2.20 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 1.901 g -? (10.0 mmol) 2-bromo-heptanoic acid nitrile 2-(6,7,8,9-

20° tetrahydro-dibenzothiophen-2-ylthio-heptanoic acid nitrile, n^ : 1.6017;

of 2.20 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-3-thiol and 2.04 g (10.0 mmol) 2-bromo-octanoic acid nitrile 2-(6.7,8,9 -tetra-20-hydro-dibenzothiophen-3-ylthio)-octanoic nitrile, 11: 1.5972.

EXAMPLE 24

A solution of 3.11 g (10.0 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic nitrile in 50 ml of abs. chloroform and 5 ml abs. ethanol is saturated at 0° to 5° with dry chlorine hydrogen gas, then stirred for 20 hours at room temperature and then evaporated at 30° in vacuo. The remaining crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid imidoethyl ester hydrochloride is boiled with a solution of 2.0 g (approx. 30 mmol) of potassium hydroxide in 40 ml of ethanol and 5 ml water 24 hours under reflux. The reaction mixture is then concentrated first, water is added and the remaining ethanol is evaporated in vacuo.

The resulting alkaline-aqueous solution is shaken with ether and then acidified with 2-N hydrochloric acid. The separated, crude acid is taken up in ether, the ether solution is washed with water, dried with magnesium sulphate and evaporated. Crystallization of the residue in hexane yields 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octane-o acid with m.p. 99 - 100 .

EXAMPLE 25

Boil 4.0 g in a round-bottomed flask with reflux condensers and stirrers

(9.3 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-hexyl-malonic acid diethyl ester in a mixture of 10 ml of 5-n sulfuric acid and 50 ml of glacial acetic acid 20 hours under backflow. After cooling, the reaction mixture is evaporated in vacuo and the remaining oil residue is distributed between ether and water. After separation of the ether phase, this is first washed with water and then extracted with 100 ml of 2% potassium hydroxide.

The alkaline solution is acidified with concentrated hydrochloric acid (pH=1) and the resulting oil is taken up in ether. The ethereal solution thus obtained is washed neutrally with water, dried with magnesium sulfate and evaporated in vacuo, obtaining the crude 2-(6,7,8,9-tetrahydrodibenzofuran-2-yloxy)-octanoic acid as a yellowish oil. After recrystallization twice in hexane, the pure acid is obtained in the form of white crystals with m.p. 99 - 100°.

Analogously, one obtains:

of 1.80 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-methyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro -dibenzofuran-2-yloxy)-propionic acid with m.p. 128 - 129° (in methanol-water);

of 2.71 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-tetradecyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro -dibenzofuran-2-yloxy)-hexadecanoic acid with m.p. 55 - 56°

(in hexane) ;

of 0.8 g (2.2 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-2-methyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro -dibenzofuran-3-yloxy)-propionic acid with m.p. 144° (in benzene-hexane);

of 1.0 g (2.33 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-2-hexyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro -dibenzofuran-3-yloxy)-octanoic acid with m.p. 78 - 79° (in hexane);

of. 2.16 g (6 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-2-tetradecyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro-dibenzofur an-3-yloxy)-hexadecanoic acid with m.p. 77.5 - 78.5°

(in methanol-water)5

of 1.34 g (3.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-2-hexyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro -dibenzofuran-2-ylthio)-octanoic acid with m.p. 92 - 93° (in hexane)5

of 2.26 g (6.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-2-methyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro -dibenzofuran-3-ylthio) -^opionic acid with m.p. 133 - 134° (in methanol-water)5 ^

of 3.57 g (8.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-2-hexyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro -dibenzo-furan-3-ylthio)-octanoic acid with m.p. 62 - 63° (in hexane);

of 3.02 g (6.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-2-decyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro -dibenzofuran-3-ylthio)-dodecanoic acid with m.p. 73.5 - 74.5°

(in hexane) ;

of 3.35 g (6.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-2-tetradecyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro -dibenzofur an- 3-ylthio)hexadecanoic acid with m.p. 69 - 70° (in methanol).

The 2-bromo-2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-hexyl-malonic acid diethyl ester used as starting material can,

starting from 2-hexyl-malonic acid diethyl ester, is prepared as follows: a) from 152.7 g (0.6 mol) of 2-hexyl-malonic acid diethyl ester is obtained by bromination with 96.0 g (1.2 mol ) bromo 2-bromo-2-hexyl-malonic acid diethyl ester as a colorless oil. KP.-03

107.5 - 108°; n£° 1.4552. '

The 2-bromo-2-methyl-malonic acid diethyl ester, the 2-bromo-2-decyl-malonic acid diethyl ester and the 2-bromo-2-tetradecyl-malonic acid diethyl ester are prepared analogously.

b) In a round-bottomed flask with reflux skirts, dropping funnel, potassium hydroxide dryer or stirrer and gas inlet stirrer, add

18.83 g (0.1 mol) of 6,7,8,9-tetrahydro-dibenzofuran-2-ol to a ; solution of 2.3 g (0.1 mol) of sodium in 200 ml of abs. ethanol under a nitrogen atmosphere. To the light brown solution of sodium phenolate thus obtained, 32.3 g (0.1 mol) of 2-bromo-2-hexyl-malonic acid diethyl ester are added dropwise while stirring and refluxed for 12 hours. After cooling, the precipitated sodium bromide is filtered off and the filtrate is evaporated in a vacuum. The brown oily residue thus obtained is taken up in ether, the ethereal solution is washed neutrally with water, dried with magnesium sulphate and

evaporated again, obtaining a yellow oil. This oil is purified by column chromatography (silica gel 0.05-0.2 mm,

in Merck, solvent benzene). The fractions containing the desired esters are combined and evaporated. After drying in high vacuum, the pure 2-(6,7,8,9-tetrahydro-dibenzo-

<:> the furan-2-yloxy)-2-hexyl-malonic acid diethyl ester as pale yellow.

? oil-, n£<2> : 1.5114.

j Analogously, one obtains:

; of 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and \ 2.53 g (10.0 mmol) 2-bromo-2-methyl-malonic acid diethyl ester 2 -(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-methyl-malonic acid diethylate, n^° : 1.5285;

of 1.80' g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 4.35 g (10.0 mmol) 2-bromo-2-tetradecyl-malonic acid diethyl ester 2 -(6,7,8,9-tetrahydro-dibegzofuran-2-yloxy)-2-tetradecyl-. malonic acid diethyl ester, n^° : 1.5033;

j of 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and f 2.53 g (0.01 mol) 2-bromo-2-methyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-2-methyl-malonic acid diethyl ester, <;n>£° <:> 1.5310;

in

\ of 3.76 g (20.0 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-3-ol and ! 6.46 g (0.02 mol) 2-bromo-2-hexyl-malonic acid diethyl ester 2-(6,7,-8,9-tetrahydro-dibenzofuran-3-yloxy)-2-hexyl-malonic acid-20

diethyl ester, n£ : 1.5181; • of 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and in 4.35 g (10.0 mmol) 2-bromo-2-tetradecyl-malonic acid diethyl ester ;2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-2-tetradecyl-malonic acid diethyl ester, n^° : 1.5053;

of 1.02 g (5.0 mmol) 6,7,8;,9-tetrahydro-dibenzofuran-2-thiol and 1.61 g (5.0 mmol) 2-bromo-2-hexyl-malonic acid diethyl ester 2 -(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-2-hexyl-malonic acid-20

diethyl ester, n^ : 1.5359;

of 2.04 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 2.53 g (10.0 mmol) 2-bromo-2-methyl-malonic acid diethyl ester 2- (6,7,8,9-tetrahygro-dibenzofuran-3-ylthio)-2-methyl-malonic acid diethyl ester, n^° : 1.5592;

of 2.04 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 3.22 g (10.0 mmol) 2-bromo-2-hexyl-malonic acid diethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-2-hexyl-malonic acid-20 diethyl ester, n^ : 1.5412;

of 2.04 g (10 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 3.79 g (10 mmol) 2-bromo-2-decyl-malonic acid diethyl ester 2-(6,7 ,8,9-tetrahydro-dibenzofuran-3-ylthio)-2-decyl-malonic acid diethyl ester;

of 2.04 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 4.35 g (10.0 mmol) 2-bromo-2-tetradecyl-malonic acid diethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-2-tetradecyl-

20

malonic acid diethyl ester, n^ : 1.5240.

EXAMPLE 26

In a round-bottomed flask with reflux skirts and stirrers, heat

3.0 g (6.9 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-hexyl-malonic acid diethyl ester in 30 ml 1-1 sodium hydroxide solution for 20 hours under reflux. After cooling, the reaction mixture is acidified with 1-1 hydrochloric acid and extracted with ether. The ethereal solution is washed neutrally with water, dried over magnesium sulphate and evaporated.

From the oily residue thus obtained, the desired 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid is obtained by crystallization in hexane. The pure 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid melts at 99.-100°.

EXAMPLE 27

A solution of 1.34 g, (3.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-2-hexyl-malonic acid diethyl ester in 15

ml of glacial acetic acid is added with 3 ml of 5-n sulfuric acid and boiled in a nitrogen atmosphere for 24 hours under reflux. The reaction mixture

is then evaporated in vacuo and the oily residue is partitioned between water and ether. After washing the ether phase with water, drying over sodium sulfate and evaporation in vacuo, a brown oil is obtained, which is purified by column chromatography on silica gel, Merck [elution with benzene and benzene-glacial acetic acid (20:1)]. The fractions containing the desired product are collected and recrystallized in hexane. 2-(6,7,8,9-tetrahydro-dibenzothiophene-2-yloxy)-octanoic acid with m.p. 90 - 91°.

Analogously, one obtains:

of 2.68 g (60 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-2-hexyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro-dibenzothio -phen-3-yloxy)-octanoic acid with m.p. 105 - 106°.

of 1.30 g (2.81 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-2-hexyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro -dibenzothiophene-2-ylthio)-octanoic acid with m.p. 91 - 92° (in hexane).

of 1.85 g (4.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio)-2-hexyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro -dibenzothiophen-3-ylthio)-octanoic acid, n^ 20 : 1.5848 after chromatographic purification on silica gel, elution with benzene and benzene-glacial acetic acid (49:1).

The 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-2-hexyl-malonic acid diethyl ester used as starting material is prepared as follows: a) To a solution of 0.258 g (11.2 mmol) sodium in 15 ml abs. of ethanol, 2.29 g (11.2 mmol) of 6,7,8,9-tetrahydro-dibenzothiophen-2-yl are added. While stirring and introducing nitrogen, 3.62 g (11.2 mmol) of 2-bromo-2-hexyl-malonic acid diethyl ester are added dropwise to this solution in 15 ml abs. ethanol and boil the reaction mixture for 4 hours under reflux. After cooling, the ethanol is evaporated in a vacuum and the residue is distributed between water and ether. The separated and water-washed ether phase is dried over magnesium sulphate and evaporated. The purification of the crude product takes place by column chromatography on silica gel [elution with benzene-hexane (2:1)]. 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-2-hexylmalonic acid diethyl ester is obtained, n°: 1.5383.

Analogously, one obtains:

of 2.04 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-3-

ol and 3.23 g (10.0 mmol) 2-bromo-2-hexyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro-dibezothiophen-3-yloxy)-2-hexyl-malonic acid diethyl ester , n^° : 1.5361;

of 1.0 g (4.54 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 1.47 g (4.54 mmol) 2-bromo-2-hexyl-malonic acid diethyl ester 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-2-hexyl-malonic acid diethyl ester, n£<u> : 1.5598;

of 2.20 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-3-

thiol and 3.23 g (10.0 mmol) 2-bromo-2-hexyl-malonic acid diethyl ester 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio)-2-hexyl-malonic acid diethyl ester , 20 : 1.5601;

EXAMPLE 28

A solution of 0.92 g of potassium hydroxide in 3 ml of water. While stirring and introducing nitrogen, the mixture is boiled for 24 hours under reflux. After evaporation of the solvent, the residue is distributed between ether and 1-n hydrochloric acid. The ether phase is washed with water, dried over sodium sulphate and evaporated in a vacuum. The thus precipitated crude mixture is separated by column chromatography on silica gel [elution with benzene and benzene: glacial acetic acid (50:1)]. 2-(6,7,8,9-tetrahydro-dibenzothiophene-2-yloxy)-octanoic acid is obtained, m.p. 90 - 91° (in hexane) and also

a little 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-2-hexyl-malonic acid (starting decomposition at 119°).

EXAMPLE 29

Boil 3.0 g in a round-bottomed flask with reflux condensers and stirrers

(7.8 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-hexyl-

in cyanoacetic acid ethyl ester in a solution of 50 ml of glacial acetic acid and 10 ml of 5-n sulfuric acid for 20 hours under reflux. After cooling, the reaction mixture is evaporated in vacuo and the remaining residue is distributed between ether and water. The ether phase is separated,

washed neutrally with water, dried with magnesium sulfate and concentrated in vacuo. The thus obtained crude 2-(6,7,8,9-

<!> tetrahydro-dibenzofuran-2-yloxy)-octanoic acid is purified by column-

in chromatography (silica gel, 0.05-0.2 mm, Merck, solvent j benzene-glacial acetic acid 85:15). The fractions containing the desired acid are purified, evaporated in vacuo and the oily residue thus obtained is crystallized twice in hexane, obtaining the pure 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)- octanoic acid with m.p. 99 - 100°.

Analogously, one obtains:

of 1.15 g (3.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-2-hexyl-cyanoacetic acid ethyl ester 2-(6,7,8,9-tetrahydro -j dibenzofuran-3-yloxy)-octanoic acid with m.p. 78 - 79° (in hexane);

in

i ■ -

i of 1.20 g (3.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-

i ylthio)-2-hexyl-cyanoacetic acid ethyl ester 2-(6,7,8,9-tetrahydro-

; dibenzofuran-2-ylthio)-octanoic acid with m.p. 92 - 93° (in hexane);

of 4.00 g (10.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-

in ylthio)-2-hexyl-cyanoacetic acid ethyl ester 2-(6,7,8,9-tetrahydro-Ldibenzofuran-3-ylthio)-octanoic acid with m.p. 62 - 63° (in hexane).

The 2-(6,7,8,9-tetrahydro-dibenzo-furan-2-yloxy)-2-hexyl-cyanoacetic acid ethyl ester used as starting material can be prepared

in read as follows:

in

a) In a round-bottomed flask with reflux skirts, dropping funnel, potassium

in hydroxide dryer tubes, stirrers and gas inlet tubes add

in man 18.8 g (0.1 mol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol to S a solution of 2.3 g (Ovl mol) sodium in 80 ml abs. ethanol under a nitrogen atmosphere. To the thus obtained brown <1> solution of sodium phenolate, while stirring, 27.6 g

(0.1 mol) 2-bromo-2-hexyl-cyanoacetic acid ethyl ester and heater

every hour to 40, 50 and 70°. It is then evaporated in vacuo to dryness. The residue is distributed between water and ether, the ether phase is separated and washed with water. After drying the ether-containing solution with magnesium sulfate, it is evaporated on

new in vacuum. The oily residue is purified by column chromatography (silica gel 0.05-0.2 mm, Merck, solvent benzene). The benzene fractions containing the desired ester are combined and evaporated. The pure 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-hexyl-cyanoacetic acid ethyl ester is obtained as a hygroscopic yellow oil.

Analogously, one obtains:

of 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 2.75 g (10.0 mmol) 2-bromo-2-hexyl-cyanoacetic acid ethyl ester 2- (6,7,8,9-tetrahydgo-dibenzofuran-3-yloxy)-2-hexyl-cyanoacetic acid ethyl ester, n^° : 1.5245;

of 6.12 g (30.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-thiol and 8.28 g (30.0 mmol) 2-bromo-2-hexyl-cyanoacetic acid ethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-2-hexyl-cyanoacetic-

20

acid ethyl ester, rip : 1.5505;

of 6.12 g (30.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 8.28 g (30.0 mmol) 2-bromo-2-hexyl-cyanoacetic acid ethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-2-hexyl-cyanoacetic acid ethyl ester, <20> : 1.5553.

EXAMPLE 30

Boil 2.11 g in a round bottom flask with reflux condensers and stirrers

(5 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-hexyl-cyanoacetic acid ethyl ester in a solution of 1.0 g of potassium hydroxide in 25 ml of ethanol and 2.5 ml of water 20 hours during back-

run. After cooling, the reaction mixture is evaporated in vacuo,

the rest is suspended for approx. ,30 ml of water, acidified with conc. hydrochloric acid and the thereby precipitated solid substance are extracted exhaustively with ether, as only an insignificant part goes into solution. The ether extracts are combined, washed nbytrally with water, dried over magnesium sulfate

and evaporated. The solid residue thus obtained (1.6 g) is purified by column chromatography (neutral silica gel, 0.05-0.2 mm, Merck, solvent benzene-glacial acetic acid 85:15). The fractions containing the desired acid are combined and evaporated. After recrystallization twice in hexane, the pure 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid with m.p. 99 - 100°.

EXAMPLE 31

In a round-bottomed flask with reflux skirts and stirrers, heat 1.0 g (2.6 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-hexyl-cyanoacetic acid ethyl ester in 20 ml of 1-n caustic soda 22 hours in reverse. After cooling, the reaction mixture is acidified with conc. hydrochloric acid and extracted with ether. The ethereal solution is washed neutrally with water, dried over magnesium sulphate and evaporated. The solid residue thus obtained contains only very little 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid. It is extracted with hot hexane, only a very small part

of the rest goes into solution. After evaporation of the hexane extract, the resulting residue is recrystallized in hexane. Pure 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid with m.p. 99 - 100°.

EXAMPLE 32

While stirring and introducing nitrogen, 2.31 g (6.0

mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-2-pentyl-cyanoacetic acid ethyl ester in a solution of 35 ml of glacial acetic acid and 7

ml 5-n sulfuric acid 48 hours under reflux. The reaction mixture is then evaporated in vacuo and the residue distributed between water and ether. The ether phase washed with water and dried over sodium sulfate is evaporated again and the crude product is purified by chromatography on silica gel [elution with benzene-glacial acetic acid (19:1)]. After recrystallization of the pure fractions in hexane, 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-heptanoic acid is obtained with m.p. 84 - 84.5°.

Analogously, one obtains:

of 1.80 g (4.51 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-2-hexyl-cyanoacetic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzothiophene -2-yloxy)-octanoic acid with m.p. 90 - 91° (in hexane).

The 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-2-pentyl-cyanoacetic acid ethyl ester used as starting material is prepared as follows: a) While stirring and introducing nitrogen, 0.588 g (12 .25 mmol) sodium hydride (50%, in mineral oil) to a solution of 2.50 g (12.25 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-3-ol in 40 ml abs. dimethylformamide. After the evolution of hydrogen has subsided, heat is continued for 5 minutes at 90° and then a solution of 3.21 g (12.25

mmol) 2-bromo-2-pentyl-cyanoacetic acid ethyl ester to the reaction mixture cooled again at room temperature. The reaction mixture is boiled for 2 1/2 hours under reflux, evaporated after cooling in vacuo and the residue distributed between water and ether. The ether phase washed with water and dried over sodium sulfate is evaporated again. The remaining crude product is purified by chromatography on silica gel [elution with benzene-hexane

(2:1)], obtaining pure 2-(6,7,8,9-tetrahydro-dibenzothiophene-3-yloxy)-2-pentyl-cyanoacetic acid ethyl ester, n£° : 1.5504...

Analogously, one obtains: ;

of 2.04 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-2-ol and 2.62 g (10.0 mmol) 2-bromo-2-hexyl-cyanoacetic acid ethyl ester 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-2-hexyl-cyanoacetic acid ethyl ester.

EXAMPLE 33 3.4 g (9.0 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-hexylmalonic acid is boiled in 34 ml of xylene for 1/2 hour under reflux. After cooling, the reaction mixture is completely evaporated in vacuo. The oily residue thus obtained is recrystallized twice in hexane. The pure 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid is obtained in the form of white needles with m.p. 99 - 100°..

Analogously, one obtains:

of 1.20 g (approx. 4.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-methyl-malonic acid 2-(6,7,8,9-tetrahydro -dibenzofuran-2-yloxy)-propionic acid with m.p. 128 - 129° (in methanol-water);

of 1.45 g (approx. 3.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-tetradecyl-malonic acid 2-(6,7,8,9-tetrahydro -dibenzo-furan-2-yloxy)-hexadecanoic acid with m.p. 55 - 56° (in hexane);

of 2.25 g (6.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-2-hexyl-malonic acid 2-(6,7,8,9-tetrahydro-dibenzofuran -3-yloxy)-octanoic acid with m.p. 78 - 79° (in hexane);

of 1.95 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-2-hexyl-malonic acid 2-(6,7,8,9-tetrahydro-dibenzofuran -2-ylthio)-octanoic acid with m.p. 92 - 93° (in hexane);

of 1.95 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-2-hexyl-malonic acid 2-(6,7,8,9-tetrahydro-dibenzofuran -3-ylthio)-octanoic acid with m.p. 62 - 63° (in hexane);

of 2.23 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-2-decyl-malonic acid 2-(6,7,8,9-tetrahydro-dibenzofuran -3-.

ylthio)-dodecanoic acid with m.p. 73.5 - 74.5° (in hexane)

The 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-hexylmalonic acid used as starting material can be obtained as follows: a) 4.0 g (9.3 mmol) 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-hexyl-malonic acid diethyl ester is boiled in a solution of

2.5 g of potassium hydroxide in 10 ml of methanol and 1 ml of water for 20 hours under reflux. The reaction mixture is now diluted with 100 ml of water, washed twice with a little ether, the aqueous phase is acidified with ice-cold concentrated hydrochloric acid and the resulting oil is extracted with ether. . After drying in high vacuum, the crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-

2-hexyl-malonic acid, which is contaminated by a little (about 2%) 2-(6,7-8,9-tetrahydrodibenzofuran-2-yloxy)-octanoic acid. The malonic acid is obtained as a tough, yellow oil, which does not crystallize and is reacted without further purification.

Analogously, one obtains from the corresponding diethyl esters: 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-methyl-malonic acid,

2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-2-tetradecyl-malonic acid,

2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-2-hexyl-malonic acid,

2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-2-hexyl-malonic acid,

The 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-2-hexyl-malonic acid and

2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-2-decyl-malonic acid,

which are further used as raw products.

EXAMPLE 34

Analogous to example 33, one obtains:

of 0.80 g (approx. 2 mmol) crude 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-2-hexyl-malonic acid 2-(6,7,8,9-tetrahydro- dibenzothiophen-2-ylthio)-octanoic acid with m.p. 91 - 92° (in hexane) 5.

of 1.20 g (approx. 3 mmol) crude 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio)-2-hexyl-malonic acid 2-(6,7,8,9-tetrahydro- dibenzothiophen-3-ylthio)-octanoic acid, 20:1.5718 after chromatographic purification on silica gel, elution with benzene and benzene-glacial acetic acid (49:1).

The starting materials are obtained, analogously to example 33 a), but only by boiling for two hours: 0.924 g (2.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-

2-hexyl-malonic acid diethyl ester or

1.386 g (3.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio)-2-hexylmalonic acid diethyl ester.

EXAMPLE 35

0.78 g (approx. 2 mmol) of crude 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-2-hexylmalonic acid is heated under a nitrogen atmosphere for 1/2 hour at 150°. The decarboxylated crude product is purified by chromatography on silica gel [elution with benzene and benzene-glacial acetic acid (19:1)]. After recrystallization of the pure fractions in hexane, 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-octanoic acid is obtained, m.p. 90 - 91°.

By heating at

240 - 250° for 5 minutes and preparation as above 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-octanoic acid with m.p. 106 - 107° (in hexane).

The starting materials are obtained analogously to example 33 a), but only with two hours of boiling of: 0.892 g (2.0 rnmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-2-hexyl-malonic acid diethyl ester or

0.892 g (2.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-2-hexyl-malonic acid diethyl ester.

EXAMPLE 36

In a round-bottomed flask with reflux skirts, potassium hydroxide drying stirrer, stirrer and gas inlet stirrer, 100 ml of abs. benzene, 12.0 g (99 mmol) thionyl chloride and 0.5 ml dimethylformamide introduced and then 9.4 g (28 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid introduced . After the acid has dissolved, boil for a further 2 hours under reflux. After cooling, the clear, yellow solution is evaporated in vacuo and the remaining, oily residue is evaporated several times with benzene. The crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid chloride thus obtained is taken up in 150 ml abs. ether and drips the ethereal solution thus obtained into 500 ml of ammonia-saturated ether, whereby a thick slurry is formed. Ammonia is introduced into the reaction mixture for a further 3 minutes, stirred for a further 10 minutes and the reaction mixture is then washed with neutral water. The ether phase is dried with magnesium sulfate and evaporated, obtaining the crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanamide in solid form. From ethanol-water the pure amide crystallizes with m.p. 130 - 131°.

Analogous to the regulation stated above, one obtains:

of 1.38 g (3.5 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-dodecanoic acid 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy )-dodecanamide with m.p. 112 - 112.5° (in ethanol)5

of 1.04 g (4.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-propionic acid 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) )-propionamide;

of 1.57 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) )-heptanamide with m.p. 145 - 146 (in ethanol);

of 1.65 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-octanoic acid 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) )-octanamide with m.p. 140 - 141° (in ethanol)5

of 1.93 g (5.0 mmol) 22-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-dodecanoic acid 2-(6,7,8,9-tetrahydro-dibezofuran-3-yloxy )-dodecanamide, m.p. 131.5 - 132.5° (in vinegar)5

of 1.73 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-octanoic acid 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio) )-octanamide, m.p. 135 - 136° (in ethanol);

of 2.77 g (8.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-octanoic acid 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio )-octanamide,

m.p. 107.5 - 109° (in ethanol-water).

EXAMPLE 37

A solution of 3 g (7.24 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-dodecanoic acid ethyl ester in 10 ml of ethanol is heated with 20 g of ammonia at a maximum pressure of 45 bar 40 hours at 100°. After evaporation and recrystallization of the residue obtained, the pure 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-dodecanamide with m.p. 131.5 - 132.5°.

EXAMPLE 38

While stirring, 1.19 g (10.0 mmol) of thionyl chloride are added in drops

to a solution of 1.73 g (5.0 mmol) of 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-octanoic acid in 25 ml of abs. benzene and 0.1 ml of dimethylformamide. The reaction mixture is boiled for 1 1/2 hours under reflux and then evaporated in vacuo. Excess thionyl chloride is removed by adding abs several times. benzene and evaporation in vacuo. The oily residue,

the crude 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-octanoic acid chloride is taken up in lOO ml abs. ether and the ether-containing solution of ammonia gas is saturated. The mixture is stirred for a further 20 minutes and the reaction mixture is then washed with water. After drying the ether phase over magnesium sulfate and evaporation in a vacuum, the crystalline crude product is recrystallized from acetone-hexane. 2-(6,7,8,9-tetrahydro-dibenzothiophene-3-yloxy)-octanamide is obtained with m.p. 142 - 143°.

Analogously, one obtains:

of 1.73 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-octanoic acid 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy )-octanamide, m.p. 116 - 117° (in methanol);

of 1.74 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-heptanoic acid 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) )-heptanamide with m.p. 150 -:150.5° (in methanol) 5

of 1.81 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophene-3-

ylthio)-octanoic acid 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio)-octanamide with m.p. 106 - 109° (in methanol).

EXAMPLE 39

A solution of 1.1 g (4.0 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid nitrile in 40 ml abs. chloroform and 2 ml abs. methanol with stirring at 5 - 8° for 10 minutes with dry hydrogen chloride and then stirred for 4 hours at room temperature. The reaction solution is then evaporated in a vacuum and the remaining oily residue is heated for approx. 3 minutes in vacuum to remove the formed methyl chloride at 90°. The solid residue thus obtained is recrystallized twice in ethanol with the addition of activated charcoal. Pure 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanamide is thus obtained in the form of white needles with m.p. 145 - 146°.

Analogously, one obtains:

of 3.11 g (10.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic nitrile 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) )-octanamide, m.p. 130 - 131° (in ethanol-water);

of 1.21 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-propionic acid nitrile 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy )-propionamide;

of 1.84 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-dodecanoic acid nitrile 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) )-dodecanamide with m.p. 112 - 112.5° (in ethanol);

of 3.11 g (10.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-octanoic acid nitrile 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) )-octanamide, m.p. 140 - 141° (in ethanol);

of 1.84 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-dodecanoic acid nitrile 2-(6,7,8,9-tetrahydro-dibenzofuran--3- yloxy)-dodecanamide with m.p. 131.5 - 132.5° (in vinegar);

of 1.64 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-octanoic acid nitrile 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio )-octanamide with m.p. 135 - 136 o (in ethanol);

of 1.64 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-octanoic nitrile 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) )-octanamide with m.p. 107.5 - 109° (in ethanol-water).

EXAMPLE 40

Through the ice-cold solution of 1.40 g (4.28 mmol) of 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-octanoic acid-nitrile in 80 ml of abs. chloroform and 4 ml abs. methanol is led to saturate dry chlorine hydrogen gas, taking care then that the temperature does not exceed 5°. The reaction mixture is allowed to stand for a further 4 hours with stirring at room temperature and is then evaporated in vacuo. The oily residue is heated for a further 10 minutes in a water jet vacuum at 90°. Thereby, methyl chloride is split off during slurrying. The desired product precipitates directly in crystalline form. After recrystallization in methanol, 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-octanamide is obtained with m.p. 116 - 117 (in methanol).

Analogously, one obtains:

of 1.50 g (4.58 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-octanoic acid nitrile 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) )-octanamide with m.p. 142 - 143° (in acetone-hexane);

of 1.25 g (3.80 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-heptanoic acid nitrile 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) )-heptanamide with m.p. 150 - 150.5° (in methanol);

of 1.72 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio)-octanoic acid nitrile 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio) )-octanamide with m.p. 106 - 109 (in methanol).

EXAMPLE 41

In a round-bottomed flask with stirrers, potassium hydroxide drying stirrer, gas introduction stirrer and thermometer, a solution of 3.11 g (10.0 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid nitrile in 50 ml abs. chloroform and 5 ml abs. ethanol at 0-5° with dry hydrogen chloride, then stirred for 20 hours at room temperature and finally evaporated at 30° in vacuum. The rest are admitted in 40

ml of dioxane, 4 ml of water are added and the solution thus obtained is stirred for 3 hours at 40°. It is then evaporated again, the residue is taken up in benzene, the benzene-containing solution is dried over magnesium sulphate and evaporated again. After one hour of drying at 100° and 0.1 torr, the crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid ethyl ester is obtained, which is purified by column chromatography (silica gel 0.05 - 0.2 mm,

Merck, solvent benzene). The benzene fractions containing the desired ester are combined and evaporated. After drying in high vacuum, the pure 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid ethyl ester is obtained as a pale yellow oil,

23

n£<J> : 1.5227.

Analogously, one obtains:

of 2.41 g (10.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-propionitrile 2-(6,7,8,9-tetrahydro-dibenzofuran-2 -yloxy)-propionic acid ethyl ester, n^° : 1.5408; of 2.97 g (10.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid nitrile 2-(6,7,8<j)9-tetrahydro-dibenzofuran-2 -yloxy)-heptanoic acid ethyl ester, n^° : 1.5241; of 3.67 g (10.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-dodecanoic acid nitrile 2-(6,7,8.9-tetrahydro-dibenzofuran-2-yloxy)- dodecanoic acid ethyl ester, <22>: 1.5133; of 4.23 g (10.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-hexadecanonitrile 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) )-hexadecanoic acid ethyl ester, rip 20 : 1.5062; . of 3.11 g (10.0 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-octanoic nitrile 2-(6,7,8,9-tetrahydro-dibenzofuran-3-<: >20

yloxy)-octanoic acid ethyl ester, n_^ : 1.5233;

t

of 3.27 g (10.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-rOctanoic nitrile 2-(6,7,8.9-tetrahydro-dibenzofuran-2-ylthio)- octanoic acid ethyl ester, <20>: 1.5465;

of 3.27 g (10.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-octanoic nitrile 2-(6,7,8.9-tetrahydro-dibenzofuran-3-ylthio)- octanoic acid ethyl ester, n^ 20 : 1.5517.

Similarly, 2.97 g (10.0 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid nitrile is obtained using 5 ml of abs. methanol instead of ethanol 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid methyl ester,

20

n£u : 1.5320.

EXAMPLE 42

3.11 g (10.0 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid nitrile is added to the mixture of 50 ml of ethanol, 5 ml of water and 3 ml of 30% aqueous hydrogen peroxide solution at 20° with 1.0 ml of 2-n caustic soda. After the evolution of oxygen has ceased, the reaction solution is heated for a further 30 minutes at 50° and then concentrated in a vacuum. The concentrate benefits

rian between chloroform and water, washes the chloroform phase with water, dries it over potassium carbonate and evaporates the solvent. The residue is crystallized in ethanol-water, obtaining 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanamide with m.p. 130 - 131°.

EXAMPLE 43

A solution of 1.50 g (4.58 mmol) of 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-octanoic nitrile in 50 ml of abs. chloroform and 5 ml abs. ethanol is saturated at 0-5° with dry hydrogen chloride, stirred for 15 hours at room temperature and then evaporated at 30° in vacuum. The residue is taken up in 20 ml of dioxane and 4 ml of water and the reaction mixture is stirred for a further 5 hours at 40 o. After evaporation in a vacuum, the reaction product is taken up in benzene, the benzene-containing solution is dried over magnesium sulphate and evaporated again. The purification of the crude product takes place by chromatography on silica gel [elution with benzene-hexane (2:1)], as

one obtains 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-

20

octanoic acid ethyl ester, : 1.5498.

Analogously, one obtains:

of 2.62 g (8.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-octanoic acid nitrile 2-(6,7,8.9--tetrahydro-dibenzothiophen-3-yloxy) -octanoic acid ethyl ester, n^ 20: 1.5481;

of 1.0 g (3.04 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-heptanoic acid nitrile 2-(6,7,8.9-tetrahydro-dibenzothiophene-2 - 20

ylthio)-heptanoic acid ethyl ester, : 1.5787;

of 1.72 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio)-octanoic nitrile 2-(6,7,8.9-tetrahydro-dibenzothiophen-3-

20

ylthio)-octanoic acid ethyl ester, 1l : 1.5754.

EXAMPLE 44

To a solution of 1.1 g (11.0 mmol) of diisopropylamine in 8 ml

abs. tetrahydrofuran, butyl lithium in hexane (5.2 ml of a 2.12 molar solution, corresponding to 11.0 mmol) is added under a nitrogen atmosphere and stirring and the temperature is kept below 0 o . To the cold basic solution obtained in this way, 1.23 g (5.0 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-acetic acid is added in small portions and further stirred under 0°. After a further 15 minutes, 2.03 ml (11.5 mmol) of hexamethylphosphoric acid triamide is added dropwise to the now yellow-coloured solution at 5 and then stirring once more for 15 minutes, the color of the solution changing to brown. It is then cooled at 0° and 0.745 ml (5.3 mmol) of n-hexyl bromide is added, whereby the temperature rises to 10°. The mixture is stirred for a further 2 hours at room temperature, then acidified at 0° with 2N hydrochloric acid, 150 ml of water is added and ether is extracted. The ethereal solution thus obtained is now extracted with approx. 40 ml of 0.5-n caustic soda, the alkaline extract is acidified again with hydrochloric acid and extracted several times with ether.

After drying over magnesium sulphate, the ether-containing solution is evaporated in a vacuum. A brown oil is thus obtained, which, in addition to the desired 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid, next to other impurities, still contains the 2-(6,7, 8,9-tetrahydro-dibenzofuran-2-yloxy)-acetic acid. The oil is purified by column chromatography [neutral silica gel 0.05 - 0.2 mm, Merck, solvent benzene-glacial acetic acid (9:1)]. The fractions containing the desired acid are combined, evaporated and the solid residue thus obtained is recrystallized twice in hexane. Pure 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid with m.p. 99 - 100°.

Analogously, one obtains:

of 1.23 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-acetic acid and 0.745 ml (5.3 mmol) hexyl bromide 2-(6,7,8 ,9-tetrahydro-dibenzofuran-3-yloxy)-octanoic acid with m.p.

78 - 79° (in hexane).

The 2-(6,7,8,9-tetrahydro-dibenzo-furan-2-yloxy)-acetic acid used as starting material is obtained as follows: a) To a solution of 1.15 g (50.0 mmol) of sodium in 20 ml abs. 9.40 g of ethanol (50.0

mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol. Then, while stirring, 9.2 g (55.0 mmol) of 2-bromoacetic acid

ethyl ester and boil for 4 hours under reflux. After

after cooling, the reaction mixture is evaporated in a vacuum and the residue distributed between water and ether. The ether phase is washed with water, dried over magnesium sulfate, evaporated and the remaining crude product is purified by column chromatography on neutral silica gel (0.05 - 0.2 mm, Merck, solvent benzene) from a small starting material. The 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-acetic acid ethyl ester obtained crystallizes in ethanol, m.p. 75 - 76°.

Analogously, one obtains:

of 3.76 g (20.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 3.67 g (22.0 mmol) 2-bromoacetic acid ethyl ester 2-(6,7,8 ,9-tetrahydro-dibenzofuran-3-yloxy)-acetic acid ethyl ester with m.p.

54 - 55° (in hexane).

b) 8.22 g (30.0 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-acetic acid ethyl ester is boiled in a solution of 3.36 g (60.0

mmol) of potassium hydroxide in 100 ml of methanol and 10 ml of water for 4 hours under reflux. After cooling, the reaction mixture is evaporated, the residue is distributed between dilute hydrochloric acid and ether, the ether phase is separated and the saline phase is extracted with ether.

The combined ether solution is washed neutrally in water, dried over magnesium sulphate and evaporated. The remaining crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-acetic acid is recrystallized in ethanol, m.p. 185 - 186°.

Analogously, one obtains:

of 4.0 g (14.5 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-acetic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzofuran-3 -yloxy)-acetic acid with m.p. 163 - 165° (in ethanol-water).

EXAMPLE 45

Analogous to example 44, one obtains:

of 1.31 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-acetic acid and 0.745 ml (5.3 mmol) hexyl bromide 2-(6,7,8 ,9-tetrahydro-dibenzofuran-2-ylthio)-octanoic acid with m.p. 92 - 93°

(in hexane).

Likewise, analogously to example 44, one obtains:

of 1.31 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-acetic acid and 0.745 ml (5.3 mmol) hexyl bromide 2-(6,7,8 ,9-tetrahydro-dibenzofuran-3-yltib)-octanoic acid with m.p. 62-63 o

(in hexane) ; :.

of 1.31 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio-

acetic acid and 1.042 g (5.3 mmol) of decylbromide 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-dodecanoic acid with m.p. 73.5 - 74.5° (in hexane).

The 2-(6,7,8,9-tetrahydro-dibenzo-furan-2-ylthio)-acetic acid used as starting material is obtained as follows: aj To a solution of 0.46 g (20.0 mmol) sodium in 40 ml abs. of ethanol, 4.08 g (20.0 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-2-thiol are added. A similarly prepared solution of the sodium salt of 2.78 g (20.0 mmol) of 2-bromoacetic acid in 80 ml abs is added to the thus obtained sodium salt solution. ethanol and boil the mixture for 4 hours under reflux. After cooling, the reaction mixture is filtered off and the filtrate is evaporated in vacuo. The residue is dissolved together with the nuttje substance in water, the aqueous solution is decolorized with activated charcoal and acidified with concentrated hydrochloric acid. The separated crude product is filtered off and recrystallized in ethanol-water. The 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-acetic acid obtained melts at 122-123°.

Analogously, one obtains:

of 4.08 g (20.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-

thiol and 2.78 g (20.0 mmol) of 2-bromoacetic acid 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-acetic acid with m.p. 103.5 - 104.5°

. Ci. ethanol-water).

EXAMPLE 46

To a -10° cooled solution of 1.11 g (11.0 mmol) diisopropylamine in 10 ml abs. tetrahydrofuran, 5.2 ml of a 2.12 molar solution of butyllithium in hexane (11.0 mmol) is added dropwise while stirring and introduction of nitrogen. The reaction mixture is then added portionwise with 1.39 g (5.0 mmol) of 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-acetic acid, whereby care is taken that the temperature does not exceed -5°. The mixture is stirred for 30 minutes at 0°, then 2.06 g (11.5 mmol) of hexamethylphosphoric triamide are added dropwise and further stirred for 30 minutes at -5 at 0°. At -5°, 0.875 g (5.3 mmol) of freshly distilled hexyl bromide is then added and stirred for a further 2 hours at room temperature. The reaction mixture is then distributed between dilute hydrochloric acid and ether. After drying the ether extract over sodium sulfate and evaporation in a vacuum, the crude product is purified by chromatography on silica gel [elution with benzene and benzene-glacial acetic acid 60:3)]. 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-octanoic acid with m.p. 91 - 92° (in hexane).

Analogously, one obtains:

of 1.39 g (5.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio)-acetic acid and 0.875 g (5.3 mmol) hexyl bromide 2-(6,7,8 ,9-tetrahydro-dibenzothiophen-3-ylthio)-octanoic acid, 20: 1.5718 after chromatographic purification on silica gel, elution with benzene and benzene-glacial acetic acid (49:1).

The starting materials are prepared analogously to example 45 a). thus one obtains: a) from 1.76 g (8.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-2-thiol and 1.112 g (8.0 mmol) bromoacetic acid 2-(6,7,8 ,9-tetrahydro-dibenzothiophen-2-ylthio)-acetic acid with m.p. 132 - 134° (in ether-hexane)5

of 1.76 g (8.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-3-thiol and 1.112 g (8.0 mmol) bromoacetic acid 2-(6,7,8,9-tetrahydro-dibenzothioph en-3-ylthio)-acetic acid.

EXAMPLE 47

Analogous to example 46, one obtains:

of 2.62 g (10.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-acetic acid and 1.70 g (10.3 mmol) hexyl bromide 2-(6,7 ,8,9-tetrahydro-dibenzothiophen-2-yloxy)-octanoic acid with m.p. 90 - 91° (in hexane);

of 2.62 g (10.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-acetic acid and 1.70 g (10.3 mmol) hexyl bromide 2-(6,7 ,-8,9-tetrahydro-dibenzothiophen-3-yloxy)-octanoic acid with m.p. 106 -

107° (in hexane)

The starting materials are prepared analogously to example 44 a) and b).

a) of 5.10 g (25.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-

ol and 4.18 g (25.0 mmol) bromoacetic acid ethyl ester are obtained

2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-acetic acid-

ethyl ester with m.p. 112 - 113° (in ethanol), and

in

i of 5.10 g (25.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-3-ol and I 4.18 g (25.0 mmol) bromoacetic acid ethyl ester 2-(6,7,8 ,9-tetrahydro-dibenzothiophen-3-yloxy)-acetic acid ethyl ester.

:"b), of 4.35 g (15.0 mmol) of 2-(6,7,8,9-tetrahydro-dibenzothiophene-2-

; yloxy)-acetic acid ethyl ester yields 2-(6,7,8,9-tetrahydro-

in dibenzothiophen-2-yloxy)-acetic acid with m.p. 218 - 220° (in ethanol), and

in

j of 4.35 g (15.0 mmol) 2-(6,7,8,9-tetrahydro-dibenzothiophene-3-

jyloxy)-acetic acid ethyl ester 2-(6,7,8,9-tetrahydro-dibenzothiophene-

in 3-yloxy)-acetic acid.

in

in

: EXAMPLE 48 7.52 g (4.0 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 14.2 g (8.0 mmol) of 1,1,1-trichloro-2-methyl -2-propanol (acetone chloroform) is dissolved in 130 ml of distilled acetone, the solution is cooled to 0 o and 4.27 g of powdered sodium hydroxide are added. (a third of a total of 12.8 g = 320 mmol). You let the temperature! while stirring for 2 hours rise to 25 . After cooling again to 0°, the second portion of 4.27 g of sodium hydroxide I is added and, following the same procedure, after 2 hours the last portion.

1 • Again, the temperature is allowed to rise to 25 o over the course of 2 hours.

The mixture is stirred for a further 5 hours at this temperature and then evaporated in the rotary evaporator. The residue is dissolved in , water, the dark solution is acidified with conc. hydrochloric acid and extracted with ether. The ether solution is extracted in turn: with 2-n sodium bicarbonate solution and the alkaline extract I is acidified. The precipitated, crude 2-(6,7,8,9-tetrahydro-dibenzofuran-2-•yloxy)-2-methyl-propionic acid is triturated twice with petroleum ether and filtered off. The thus purified acid is dissolved in 100 ml of methanol, the solution is decoloured with activated carbon and then ?90 ml of water is added. The separated crystals are filtered off and recrystallized several times in methanol-water, m.p. until the pure acid is 136.5 - 138°.

Analogously, using the same amount of 1,1,1-trichloro-2-methyl-2-propanol, sodium hydroxide and acetone gives: from 7.52 g (4.0 mmol) 6,7,8,9-tetrahyde* o-dibenzofuran-3-ol 2-(6,7,8,9-tetrahydro-dibenzofuran-3-yloxy)-2-methyl-propionic acid with m.p. 78 - 80° (in hexane); of 8.16 g (4.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-thiol 2-(6,7,8,9-tetrahydro-dibenzofuran-2-ylthio)-2-methyl-propionic acid with m.p. 146 - 147 (in ether-hexane);

of 8.16 g (4.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol 2-(6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)-2-methyl- propionic acid;

of 8.16 g (4.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-2-ol 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-2-methyl- propionic acid with m.p. 121 - 122° (in methylene chloride-hexane);

of 8.16 g (4.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-3-ol 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-2-methyl- propionic acid;

of 8.80 g (4.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-2-thiol 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio)-2-methyl- propionic acid;

of 8.80 g (4.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-3-thiol 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio)-2-methyl- propionic acid.

EXAMPLE 49

1.1 g (3.5 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-heptanoic acid is dissolved in 20 ml of abs. ethanol. A solution of 69 g (3.0 mmol) of sodium is added to the solution obtained

in 5 ml abs. ethanol, evaporate to dryness and grate the white, solid residue with approx. 20 ml of ether. It is then filtered off and washed with ether. The pure sodium salt is obtained as a white powder, which melts between 290 - 308° during decomposition.

EXAMPLE 50

Analogous to example 49, one obtains:

of 3.465 g (10.0 mmol) of 2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy)-octanoic acid the sodium salt of 2-(6,7,8,9-tetrahydro-dibenzothiophen-3- yloxy)-octanoic acid with m.p. 320 - 322°.

EXAMPLE 51

110 mg (2.75 mmol) calcium is added to 10 ml of water under a nitrogen atmosphere. To the calcium hydroxide suspension thus obtained, 2.05 g (6.22 mmol) of 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid in 50 ml of methanol are added and the mixture is boiled for 15 minutes under reflux . After cooling, the white suspension thus obtained is concentrated to approx. 20 ml, the precipitated, crude calcium salt is suctioned off and washed with a little ether. It is then extracted three times with 120 ml of boiling methanol each time. JThe methanol extracts are combined, filtered and concentrated to approx. 20 ml, whereby the calcium salt crystallizes out. The methanol phase is further diluted with approx. 30 ml of ether, then suck off the crystalline seed and wash it with ether. After drying in a high vacuum, the pure calcium salt of 2-(6,7,8,9-tetrahydro-dibenzofuran-2-yloxy)-octanoic acid is obtained, which melts

at 305 - 315° during cleavage.

EXAMPLE 52

To one by splitting 137 mg (3.42 mmol) calcium in 15 ml

water prepared suspension of calcium hydroxide, a solution of 2.50 g (7.2 mmol) of 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-octanoic acid in 80 ml is added with stirring and the introduction of nitrogen methanol. The reaction mixture is refluxed for 15 minutes and concentrated in vacuo. The precipitated crude calcium salt is filtered off, washed with ether and recrystallized twice from abs. methanol. One thus obtains the pure calcium salt of 2-(6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy)-octane-

Examined compounds

XXI 2-(6,7,8,9-tetrahydrodibenzofuran-2-yloxy)-2-cyclohexylacetic acid

XXII 2-(6,7,8,9-tetrahydrodibenzofuran-3-yloxy)-2-cyclohexylacetic acid

XXIII 2-(6,7,8?9-tetrahydrodibenzothiophen-3-yloxy)-octanoic acid .-■

XXIV 2-(6,7,8,9-tetrahydrodibenzothiophen-2-ylthio)-octanoic acid

XXV 2-(6,7,8,9-tetrahydrodibenzothiophen-3-ylthio)-octanoic acid.

Results obtained

Claims (1)

Analogous method for the production of hypolipemically active aryloxy- or arylthioalkanoic acids, of the general formula I where R^ means an alkyl group with at most 14 carbon atoms or a cycloalkyl group with 5-7 carbon atoms, R2 hydrogen or the methyl group, R^ the hydroxyl group, in which the hydrogen atom is possibly replaced by an alkali or an alkaline earth metal atom, an alkoxy group with at most 3 carbon atoms or the amino group, X and Y independently of each other oxygen or sulphur, characterized by a) reacting an alkali metal salt of a phenol or a thiophenol of the general formula II, where X and Y have those specified under formula I meanings, with a compound of the general formula III, where R 1 , R 2 and R 3 have the meanings given under the general formula I and A means halogen, an alkylsulfonyloxy or an arylsulfonyloxy group, or b) for the production of aryloxy- or arylthioalkanoic acids with the general formula I, where R^ denotes the hydroxyl group, or their alkali and alkaline earth metal salts, hydrolyze or saponify a functional derivative of such an acid, c) for the production of aryloxy .- or arylthioalkanoic acids of the general formula I, where R^ denotes the hydroxyl group and R 2 hydrogen or their alkali and alkaline earth metal salts, heat under hydrolyzing conditions the compound of the general formula IV, where R^, X and Y have the meanings given under formula I, and Z^ and independently of each other means lower-alkyl carbonyl or nitrile groups, , until one of the groups Z-^ or Z2 is split off and . the other is converted into.a carboxyl group or an alkali or earth alkali metal salt thereof, or d) for the production of aryloxy or arylthioalkanoic acids, of the general formula I, where R 2 denotes hydrogen, heat connection with the general formula V, where R^, R^, X and Y have the meanings given under formula I, until cleavage of the equimolar amount of carbon dioxide takes place, or e) for the production of aryloxy- or arylthioalkanoic acid amides of the general formula I, where R^ denotes the amino group, react with an aryloxy or arylthioalkanoic acid derivative with the general formula VI where R 1 , R 2 , X and Y have the meanings given under formula I/ and B means halogen or an alkoxy group, with ammonia, or f) for the production of aryloxy or arylthioalkanoic acid amides of the general formula I, where R^ denotes the amino group, anchors water to a nitrile of the general formula VII, where R 1 , R 2 / X and Y have the meanings given under formula I, or g) for the production of aryloxy- or arylthioalkanoic acid esters of the general formula I, where R^ denotes an alkoxy group with at most 3 C - atoms, -.; reacts a nitrile of the general formula VII, where R^,' R2, X and Y have the meanings given under formula I, in the presence of water and mineral acid, with an alkanol with at most 3 C atoms, or h) for the production of aryloxy- or arylthioalkanoic acids of the general formula I, where R^ denotes the hydroxyl group or their salts with alkali metals, react with a bis-alkali metal or bis-halogenmagnesium compound of a carboxylic acid of the general formula VIII, where X, Y and R2 have those under the general formula I stated meanings, with a substantially equimolar amount of a compound of the general formula IX, where it has the meaning given under formula I, and A means halogen, an alkylsulfonyloxy or an arylsulfonyloxy group, wherein the jpyrene of formula I is released from a compound obtained from the bis-halogen magnesium compound of compound VIII with reaction with an acid, or i) for the production of aryloxy- or arylthioalkanoic acids of the general formula I, where R2 is the methyl group and R^ means the hydroxyl group, and their salts with alkali and alkaline earth metals, react with a compound of the general formula II indicated under a) where X and Y have the meanings indicated there, with a chlorine and/or bromine tri- or tetra-substituted methane and a ketone of the general formula X, where R^ has the meaning given under formula I, or with the reaction product of both of the latter components, i.e. a compound of the general formula XI, where Hal means chlorine or bromine and R1 has the meaning given under formula I, in the presence of at least four times the molar amount of a strong base, after which a salt obtained, which is not an alkali or alkaline earth metal salt, is converted to an alkali or alkaline earth metal salt or the free acid, and if desired, a free acid obtained is converted to an alkali or alkaline earth metal salt, or an alkali or alkaline earth metal salt obtained is converted to the free acid or another alkali or alkaline earth metal salt.