DE2113455A1 - Process for the preparation of new aryloxy and arylthioalkanoic acids, their salts and functional derivatives - Google Patents

Description

CIBA-GEIQY AG. CH-4002 Basel

CIBA-GEIGY

Dr. F. Zumsteln sen. - Dr. E. Assmann 4 - 3 2 7 9 ^Λ

Dr.lt Koenigsberger - Dipl. Phys. R. Holzbauer

Dr. F. Zumstein jun. _A , ... «.. r- -

P ο t a η I α η w ΰ II « 2 1 1 3 4 5 5

8 Mönchen 2, Bräiihausstroße 4 / IU. **

Process for the production of new aryloxy and arylthio

alkanoic acids, their salts and functional derivatives

The present invention relates to new aryloxy and arylthio-alkanoic acids, their salts and functional Derivatives, processes for the preparation of the new compounds, medicaments which contain the new compounds and their use.

Compounds of general formula I,

XC-COR ₃ Ί). «2

in which

R, an alkyl group with a maximum of 14 carbon atoms or a cycloalkyl group with 5-7 carbon atoms,

R _{2 is} hydrogen or the methyl group,

R-, the hydroxyl group in which the hydrogen atom can be replaced by an alkali metal or an alkaline earth metal,

109841/1978

an alkyloxy group having at most 3 carbon atoms or the amino group and

X and Y independently of one another are oxygen or sulfur,

have not yet become known.

The compounds of general formula I, such as 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid, the 2- (6,7,8,9-Tetrahydro-dibenzofuran-2-yloxy) -dodecanoic acid, the 2- (6,7, e ^ -Tetrahydro-dibenzofuran-S-yloxy) -octanoic acid, the 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-yloxy) -dodecanoic acid, the 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-ylthio) -octanoic acid, the 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-ylthio) -dodecanoic acid, the 2- (6,7,8,9-Tetrahydro-dibenzofuran-2-ylthio) -octanoic acid, the 2- (6,7,8,9-Tetrahydro-dibenzothiophen-3-yloxy) -octanoic acid, the 2- (6,7,8,9-Tetrahydro-dibenzothiophen-3-ylthio) -octanoic acid and the 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) -octanoic acid, have valuable pharmacological properties and a high therapeutic index. When administered orally, they show, in particular, hypolipemic efficacy, which can e.g. in the lowering of cholesterol and triglyceride levels in the blood and liver with repeated administration in doses of 2 times 10 mg / kg per which can be detected in male rats using standard methods. The total cholesterol is determined according to R. Richterich and K. Lauber [cf. Klin. Wochenschrift 40, 1252-1256 (1962)] determined directly in the serum. Furthermore, according to J. Folch et al. [see. J.Biol.Chem. 226, 497 (1957)] serum and liver lipids

109841/1978

extracted and triglycerides and total cholesterol with the auto analyzer according to G. Kessler and H. Lederer [cf. Automation in Analytical Chemistry (1965), Technicon GmbH, Frankfurt / Main, pages 863-872, or W.D. block et al., ibid. Pages 970-971].

The new compounds are characterized by only a low activity compared to the hypolipemic activity hepatomegal effect.

In the compounds of general formula I, R 1 is an alkyl group with a maximum of 14 carbon atoms e.g. the methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, 2,2-dimethyl-propyl, Hexyl, isohexyl, 3,3-dimethyl-butyl, heptyl, nonyl, Decyl, undecyl, dodecyl, tridecyl or tetradecyl group and as the cycloalkyl group having 5-7 carbon atoms, for example, cyclopentyl, cyclohexyl or cycloheptyl group.

109841/1978

The new compounds of the general formula I are prepared according to the invention in such a way that an alkali metal salt is used of a phenol or thiophenol of the general formula II

(H)

in which X and Y have the meaning given under the general formula I, with a compound of the general formula III,

A-C- CORo (III)

I. R ₂

in which R,, R ₂ and R, which have the meaning given under the general formula I and A is halogen, an alkylsulfonyloxy or an arylsulfonyloxy group, is reacted. The reaction is preferably carried out in a solvent or diluent. Such solvents or diluents are, for example, lower alkanols, such as ethanol, or solvents free of hydroxyl groups, such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide or N, N, N ', N', N ¹ ', N ¹ '-Hexamethyl-phosphoric acid triamide.

The reaction temperatures are between 50 and 150 °, preferably at the boiling point of the solvent used. The under

109841/1978

The boiling temperature of the solvent that can be achieved under normal conditions can, if desired, be increased by working in a closed vessel. The alkali metal salts of phenols or thiophenols of the general formula II and the alkali metal salts of the carboxylic acids encompassed by the general formula III are preferably formed in situ, for example with the aid of an alkali metal alcoholate, hydroxide,: or hydride, depending on whether or not an anhydrous alkanol, or a hydroxyl-solution ι is medium used as the reaction medium. Instead of an alkali metal hydride, it is also possible to use a corresponding amide, for example sodium amide.

The phenols or thiophenols of the general formula to be used as starting materials according to the invention II, namely the 6,7,8,9-tetrahydro-dibenzofuran-2-ol, the 6,7,8,9-tetrahydro-dibenzofuran-3-ol, the 6,7,8,9-tetrahydrodibenzofuran-2- thiol, the 6,7,8,9-tetrahydro-dibenzofuran-3-thiol, 6,7,8,9-Tetrahydro-dibenzothiophen-2-ol, 6,7,8,9-Tetrahydrodibenzothiophen-3-ol, the 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and the 6,7,8,9-tetrahydro-dibenzothiophene-3-thiol can can be obtained by various methods. For example, the 6,7,8,9-tetrahydro-dibenzofuran-2-ol can be easily Way to represent by adding 1-morpholino-eyelohexen- (1) and p-benzoquinone reacted at room temperature in methylene chloride and the initially obtained 5a, 6,7,8,9,9a-hexahydro-sa-morpholino-dibenzofuran-2-ol by boiling in aqueous hydrochloric acid to the 6,7,8,9-tetrahydr splits o-dibenzofuran-2-ol and morpholine hydrochloride. (See G. Doraschke, J.Prakt. Chem. J2, 144-157 (1966) 1

109841/1978

Another possibility for the division of 6,7,8,9-tetrahydro-dibenzofuran-2-ol, which also includes the production of 6,7, · 8,9-tetrahydro-dibenzofuran-3-ol, consists in that 2-chloro-cyclohexanone or 2-bromocyclohexanone with an alkali metal salt of hydroehinone monomethyl ether or resorein monomethyl ether converts and the initially obtained 2- (4-methoxyphenoxy) -cyclohexanone or 2- (3-methoxyphenoxy) -cyclohexanone then in the presence of an acidic catalyst, e.g. Phosphoric acid or sulfuric acid, into the 2-methoxy-6,7,8,9-tetrahydro- or 3-methoxy-6,7,8,9-tetrahydro-dibenzofuran transferred and then split off the methyl group. The methyl group can be split off, for example, by boiling the substances in a mixture of conc. Hydrobromic acid and glacial acetic acid or by heating with pyridine hydrochloride.

The 6,7,8,9-tetrahydro-dibenzofuran-2-thiol and the 6,7,8,9-tetrahydro-dibenzofuran-3-thiol can easily Way starting from the corresponding 2- or 3-hydroxy compounds be obtained by reacting this with a NjN-dialkyl-thiocarbamic acid chloride, and the 2- or 3-position Ν, Ν-dialkyl-thiocarbainoyloxy group rearranged to the N, N-dialkyl-carbamoylthio group and then hydrolyzed. The rearrangement is expedient by heating the substances to temperatures for several hours from 250-300 ° [cf. also M.S. Newman and H.A. Karnes J. Org. Chem. 31, 3980-3984, (1966)}.

For the preparation of 6,7,8,9-tetrahydro-dibenzothiophen-2-ol and 6,7,8,9-Tetrah3 ^ dro-dibenzothiophen-3-ol for example, 2-chloro- or 2-bromo-cyclohexanone is used

109841/1978 SAD original

with an alkali salt of 4-Msthox> - or 3-methoxy-thiophenol to 2- (4-methoxyphenylthio) -cyclohexanone or 2- (3-methoxyphenylthio) -cyclohexanone around and leads these compounds by subsequent ring closure with phosphoric acid and Ether cleavage with pyridine hydrochloride into 6,7,8,9-tetrahydro-dibenzothiophene-2- or -3-ol over. Finally, the 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol can be obtained from these compounds and the 6,7,8,9-tetrahydro-dibenzo-thiophene-3-thiol again by reaction with Ν, Ν-dialkyl-thiocarbamic acid chloride, Rearrangement of those present in the 2- or 3-position Ν, Ν-dialkyl-thiocarbamoyloxy group into the Ν, Ν-dialkyl-carbamoylthio group and subsequent hydrolysis can be obtained. [See. M.S. Newman and H.S. Karnes, J. org. Chem. 3JL, 3980-3984,

Those included in the general formula II as Starting materials required phenols and thiophenols of the general formula Ila'und Hb,

(Ha)

(Hb)

in which X and Y have the meaning given under the general formula I, as well as the 6,7,8,9-tetrahydro-dibenzofuran-2-thiol have not yet become known.

109841/1978

The starting materials of the general formula III, which comprises chlorides and bromides derived from 2-hydroxyalkanoic acids, alkanoic acid esters and alkanoic acid amides, can be prepared in a manner analogous to that of ethyl 2-bromopropionate [cf. Ann. 197 , 13 (1879) j. The alkyl or aryl sulfonic acid esters also encompassed by the general formula III can, starting from the bromides thus represented, by reaction with corresponding sulfonic acid salts or by reacting 2-hydroxyalkanoic acids, esters or amides with an alkyl or aryl sulfonic acid chloride in the presence of Alkali can be obtained. ct-Haloarboxylic acids can also be represented by the well-known α-halogenation of carboxylic acids. Starting from these, the corresponding lower alkyl esters and the amides likewise encompassed by the general formula III are easily accessible in a manner known per se.

The aryloxy or arylthioalkanoic acids of the general formula Ia included in the general formula I,

in which R ,, R ^ _5, X and Y have the meaning given under the general formula I, and their salts with alkali and alkaline earth metals can be prepared by a second process according to the invention by hydrolyzing a functional derivative of such an acid.

109841/1978

The functional derivatives of aryloxy or arylthioalkanoic acids of the general formula Ia are used their esters, e.g. lower alkyl esters or the cyclohexyl, phenyl or benzyl esters, as well as nitriles, amides and lower imido alkyl esters into consideration. This functional Derivatives of carboxylic acids of the general formula Ia can be obtained by heating in an aqueous mineral acid, for example by boiling in 60-70% sulfuric acid or in a mixture of e.g. 6-n. hydrochloric acid and glacial acetic acid, can be hydrolyzed. The free carboxylic acids obtained in this procedure of the general Formula Ia can, if desired, in a

Alkali or alkaline earth salt are transferred. When performing the method with dilute mineral acids a solubilizer must be added due to the poor solubility of the starting materials in water.

109841/1978

be set. As such, water-miscible, organic solvents come into question, such as lower alkenols, Tetrahydrofuran or, as already mentioned, glacial acetic acid. The hydrolysis can, however, also in an alkaline medium, for example by heating in alkanolic or aqueous-alkanolic alkali hydroxide solutions to temperatures between approx 50 ° and the boiling point of the reaction medium used can be carried out. From the in this way of working directly The alkali metal salts obtained can, if desired, be obtained by the free acids of the general formula for example, the alkali salts are dissolved in water and mineral acid is added. The required as starting materials Functional derivatives of carboxylic acids of the general formula Ia can be obtained analogously to the first process by adding an alkali salt of a phenol or thiophenol of the general formulas with corresponding 2-bromoalkanoic acid esters, -amides and nitriles. Starting from the nitriles obtained in this way, can also the imidoalkyl esters, which can also be used as starting materials, by reaction with an alkanol in the presence of hydrogen chloride getting produced. Another method of preparation of functional derivatives of the carboxylic acids of the general Formula Ia also consists of monoesters or monoamides of corresponding substituted aryloxy or Arylthiomalonic acids or corresponding substituted aryloxy or arylthiocyanoacetic acids are decarboxylated.

109841/1978

-U-

A third process according to the invention gives aryloxy- or arylthio-alkanoic acids of the general formula Ib,

X - CH - COOH (Ib) H

in which R *, X and Y are those given under the general formula I. Have meaning, and their salts with alkali or alkaline earth metals by adding compounds of the general formula IV,

. _v _ TX-CZ, (IV)

in which R-,, X xmd Y have the meaning given under the general formula I and Z, and Z _? independently of one another are lower alkoxycarbonyl or nitrile groups, heated under hydrolyzing conditions until one of the groups Z or Z2 is completely hydrolyzed and hydrogen is present instead of the other.

109841/1978

According to one embodiment of this according to the invention In the process, compounds of the general formula IV are heated in an aqueous mineral acid, for example 60-70% strength

Sulfuric acid or conc. Hydrochloric acid and leads the obtained Carboxylic acid of the general formula Ib, if desired, in a Alkali or alkaline earth salt over. If necessary, the reaction is carried out in the presence of an inert, water-miscible, organic solvent, which serves as a solubilizer for the starting materials, which are sparingly soluble in water, carried out. As such solvents, for example, lower alkenols, tetrahydrofuran, glacial acetic acid and others can be used.

According to a further embodiment of this according to the invention Process heats compounds of the general formula IV with alkanolic alkali hydroxide, for example methanolic potassium hydroxide solution or in aqueous-alkanolic alkali metal hydroxide and carries the alkali metal salts obtained in this way from carboxylic acids of the general formula Ib to the free acids, if desired. When performing the procedure in alkaline medium, mixtures are sometimes obtained in which In addition to the desired end product, incompletely saponified and incompletely decarboxylated intermediates are also present. This can be done by subsequent heating with a water-based Mineral acid * optionally in the presence of a water-miscible, organic solvent according to the first embodiment of the process into uniform aryloxy or arylthioalkane acids the general formula Ib can be converted.

1 0 8 B A 1/1 9 7 8

Substituted malonic acid dialkyl esters are used to carry out the process of the general formula IV boiled under reflux for a few hours in the reaction media mentioned. That too Malononitriles falling under the general formula IV and the corresponding cyanoacetic esters are reacted analogously and require but usually more vigorous reaction conditions and longer reaction times. In this case, the inventive If necessary, the reaction can be carried out in a closed reaction vessel under pressure.

The 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-dibenzothiophen-2-yloxy-, 6 * 7,8,9-tetrahydro-dibenzothiophen-3-yloxy-, 6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio- and 6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio-malonic acid ester, -malonitriles and -cyanoacetic acid alkyl esters are themselves new connections. You can, for example, by reacting alkali salts of 6,7,8,9-tetrahydro-dibenzofuran-2-ol, of 6,7,8,9-tetrahydro-dibenzofuran-3-ol, 6,7,8,9-tetrahydro-dibenzofuran-2-thiol, 6,7,8,9-tetrahydro-dibenzofuran-3-thiol , of 6,7,8,9-tetrahydro-dibenzothiophen-2-ol, 6,7,8,9-tetrahydro-dibenzothiophen-3-ol, 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 6,7,8,9-tetrahydrodibenzothiophene-3-thiol, with R.-substituted bromomalonic acid dialkyl esters, Bromo cyanoacetic acid alkyl esters or bread malonic acid nitriles can be obtained. Some of the bromine compounds mentioned are known, e.g. the diethyl bromopropyl malonic acid {see. A.W. Dox.

10 9 8 41/19 7 8

- .14 -

and L. Joder, J. Am. Chem. Soc. A ^, 1578-1581 (1922)]. Further Connections of this type can be made analogously.

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

X-GH-COR

in which R, R «, X and Y are those under the general formula I. have given meaning, can be obtained by adding a compound of the general formula V,

rr — r> -2 ^χ ■ ^c - ^C0R 3 ^<v)

I υ ί J COOH

in which R ^, R-, X and Y are those under the general formula I. have given meaning, heated until the splitting off of the equimolar amount of carbon dioxide.

109841/1978

The compounds of the general formula V can be used to split off carbon dioxide either in bulk or but also in an inert solvent, for example toluene or xylene, heated to temperatures of 100-150 ° will. The compounds of the general formula V can be prepared, for example, by adding esters of malonic acid or the malonamic acid completely or partially saponified. The malonamic acid can be formed by the addition of water to the nitrile group the corresponding cyanoacetic acid ester and immediately subsequent saponification of the ester group can be obtained. For the preparation of alkali metal salts of the carboxylic acids of the general formula Ic, acidic salts are preferably used of the malonic acids falling under the general formula V, they are heated until the equimolar amount of carbon dioxide is split off and, if desired, sets from the salt obtained the Free carboxylic acid falling under the general formula Ic.

The aryloxy- or arylthioalkanoic acid amides of the general formula Id falling under the general formula I,

(Id)

Il I I Y "I

in which R ^ R ₂ , X and Y have the meaning given under the general formula I, can be prepared by a fifth process according to the invention that an aryloxy or arylthioalkanoic acid derivative of the general formula VI,

ρ 0

-. '■ -_ X-C-C-B (VI)

r \ r \

- 16 - £ I I O * t O

in which R ₁ , R 2, X and Y have the meaning given under the general formula I and B is halogen or an alkoxy group, is reacted 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 ammonia is passed in; Acid halides react even at room temperature, while the inhalation of the esters generally requires higher temperatures. The solvents used in the reaction of the acid halides falling under the general formula VI with ammonia are ethereal liquids, such as diethyl ether, tetrahydrofuran, or hydrocarbons, such as benzene, toluene, etc., or chlorinated hydrocarbons, such as chlorine.

roform and methylene chloride, into consideration. When implementing the also falling under the general formula VI with esters

Ammonia are in addition to the higher ethers already mentioned and Hydrocarbons also lower alkenols, such as methanol or AethanoL, are suitable as solvents. The implementation takes place e.g. by heating the ammonia-saturated solutions of the esters in the solvents mentioned under reflux or if necessary under pressure in a closed vessel,

The S-Mure halides used as starting materials of the general formula VI, starting from the corresponding carboxylic acids by reaction with thionyl chloride or phosphorus pentachloride, Phosphorus trichloride or PhosphorOKychlorid obtained will. The compounds of the general formula VI to-

OWGIMAL INSPECTED

Q ύ £ ü 11 # 1 % ^ 3 -

underlying free carboxylic acids as well as those of this Formula encompassed esters can for their part analogously to the first process by reacting alkali metal salts of the corresponding Phenols or thiophenols with α-halides of corresponding alkanoic acids or their lower alkyl esters are represented.

The aryloxy- or arylthioalkanoic acid amides of the general formula Id encompassed by the general formula I,

^R l

X-C- CONH (Id)

H '
R ₂

in which R-,, R «» X and Y are those under the general formula I Have given meaning can be obtained by a sixth inventive method that one on a nitrile of the general formula VII,

(VII)

OWGINAL INSPECTED

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in which R ,, R «, X and Y have the meaning given under the general formula I _s water is deposited. This process can be carried out in such a way that the nitrile of the general formula VIl used as starting material is dissolved in a strong mineral acid, for example sulfuric acid, which contains an amount of water sufficient to form the amide, and the solution for 1/2 to 1 hour bsi Stirring temperatures between 20 and 60 °. This reaction can, if desired, also be carried out in the presence of a solvent, for example ether or tetrahydrofuran. Another possibility for carrying out the reaction according to the invention consists in dissolving a nitrile of the general formula VII in moist ether and introducing gaseous hydrogen chloride. According to a further variant of the process according to the invention, a nitrile of the general formula VII is reacted with hydrogen peroxide in an alkaline medium. The reaction is carried out in an aqueous medium _g is said to be noted however that this a sufficient amount of a water miscible organic solvent for example a lower alkenol ₉

109841/197

contains, which ensures the solubility of a nitrile of the general formula VII. According to another variant of the process according to the invention, a nitrile is the general formula VII by dissolving in an anhydrous, lower alkanol and initially passing in hydrogen chloride converted into the imidoalkyl ester hydrochloride and then by heating to temperatures of 80-130 °, preferably 90-100 °, split into an amide of the general formula Id and alkyl chloride.

The aryloxy or arylthioalkanoic acid esters of the general formula Ie encompassed by the general formula I

XC- COOR ₀ ¹ (Ie) ι j

JH

in which R ₁ , R ₂ , X and Y have the meaning given under the general formula I and R ^ 'denotes a lower alkyl radical with 1-3 carbon atoms, can be prepared according to the invention by a nitrile of the general formula VII,

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in which EL, R ₃₉ X and Y have the meaning given under the general formula I, reacts with a lower alkanol in the presence of water and mineral acid. Several variants are possible for carrying out the method according to the invention. .

For example, the nitrile of the general formula VII

and water in the presence of an equimolar amount of sulfuric acid / with an excess reflux in lower alkanol. The end product is isolated by diluting the reaction mixture with Water, the ester of the general formula Ie, which is sparingly soluble in this medium, separating out as a crude product.

According to a further embodiment of the inventive method can ■ the nitrile of the general formula VII by reaction with a lower alkanol in the presence of hydrogen chloride in the first Imidoesterhydrochlorid ran down and then hydrolyzing this to an ester of the general formula Ie. The nitrile is advantageously converted into the imidoester hydrochloride in a solvent. Excess alkanol, ether or chloroform, for example, can serve as such. Finally, water can also initially be added to a nitrile of the general formula VII and the amide obtained can be subjected to alcoholysis in the presence of a mineral acid. The addition of water to the nitrile is expediently carried out in 80-95% strength sulfuric acid and added to the resulting solution of the nitride

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add an excess of alkanol in sulfuric acid and boil the mixture at the reflux. The easiest way to isolate the end product is to dilute the reaction mixture with water, the desired ester separating out as a crude product.

The nitrile of the general formula VII used as starting material can likewise be converted by reaction analogously to the first process an alkali salt of a corresponding phenol or thiophenol can be obtained with an α-haloalkanoic acid nitrile.

The aryloxy- or arylthioalkane murs of the general formula Ia given above, included in the general formula I, in which R-. , R «» X and Y are those under the general formula I. Have given meaning, and their salts with alkali and alkaline earth metals are prepared by an eighth process by a bis-alkali metal or bis-halogen magnesium compound of a Carboxylic acid of the general formula VIII,

(VIII)

U It ι

■ Υ

in which X, Y and R "have the meaning given under the formula I. have, with the substantially mquimolar amount of a compound of the general formula IX,

R ₁ -A (IX)

in which R. has the meaning given under formula I and A is halogen, an alkylsulfonyloxy or an arylsulfonyloxy group means, converts, optionally from the resulting salt of a carboxylic acid of the general formula Ia the latter releases and, if desired, again in an alkali or Erdalkalimetatlsälz transferred. As a bis-alkali metal compound

109841/1978 originally inspected

In particular, the bis-lithium compounds are used as fertilizers bis-sodium compounds are also possible. For example, diisopropylamine and butyllithium are first formed at about -10 ° to 0 ° in a tetrahydrofuran-henan mixture, the lithium diisopropylamide, then adds the carboxylic acid of the general formula VIII, then an at least equimolar amount of hexamethylphosphoric triamide and finally the compound of the general formula IX and then carries out the reaction at room temperature over. The addition of hexamethylphosphoric triamide can optionally be omitted, especially when using Starting materials with a methyl group as R «. After a Another embodiment of the process is formed from sodium amide suspensions in liquid ammonia, which in turn is made in situ from ammoniacal sodium solutions by adding catalytic Quantities of iron (III) nitrate and stir until the blue color of the metal solution were obtained, and carboxylic acids of the general formula VIII the bis-sodium compounds of the latter and sets these with compounds of the general Formula IX, which is added dissolved in ether or tetrahydrofuran to. . . .

Bis-halogen magnesium compounds of carboxylic acids of the general formula VIII is obtained, for example, by um-. Deposition of these acids with a double molar amount of isopropyl magnesium bromide or isopropyl magnesium chloride in an ethereal solution at room temperature and a reaction time of approx.

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4-15 hours. The reaction with the compounds of the general formula IX is then preferably likewise carried out in ether or another ethereal solvent, such as e.g. tetrahydrofuran, at room temperature to the boiling point of the reaction medium.

The carboxylic acids of the general formula VIII, in which R _{0 is} a methyl group, which are required as starting materials, are new substances which are encompassed by the general formula I and can be prepared by the above-mentioned processes, preferably by the first and second processes.

The carboxylic acids required as starting materials and included in the general formula VIII the general formula Villa,

X - CH ₀ - CO - OH

² (villa)

in which X and Y have the meaning given under formula I, are also new substances. They are produced by, for example, analogous to the first process, an alkali metal

109841/1978

salt of a compound of the general formula II with a haloacetic acid or a lower alkyl haloacetate and the lower one obtained in the latter case Alkyl esters hydrolyzed analogously to the second process.

In the compounds of the general formula IX, A as halogen is preferably bromine, and also iodine or chlorine as Alkylsulfonyloxy group e.g. the methanesulfonyloxy group, and as Arylsulfonyloxy group e.g. the p-toluenesulfonyloxy group.

A ninth process is used to prepare the aryloxy or arylthioalkanoic acids included in general formula I the general formula If,

^R l

-JX-C-CO-OH (If)

-JH CH ₃

in which X ₅ Y and R- those given under the formula I.

Have meaning, and their salts with alkali and alkaline earth metals by mixing a compound of the general formula II given above, in which X and Y have the meaning given there, with a methane tri- or tetrasubstituted by chlorine and / or bromine and a ketone of the general form IX, t * J / * \ ~

in which R has the meaning given under formula I, or with the reaction product of the latter two components, a compound of the general formula XI,

! 3 .Ar
HO-C- CWal "(XI)

1/1978

in which R has the meaning given under formula I. and Hal is chlorine or bromine, reacts in the presence of at least four times the molar amount of a strong base, if desired from the resulting salt of a carboxylic acid of the general formula If, the latter liberates and, if desired, again converted into an alkali or alkaline earth metal salt. The reaction is preferably carried out in an excess of ketone general formula X carried out as the reaction medium. Even when using starting materials of the general formula XI, the corresponding ketone is preferably used as the solvent. The reaction temperature is preferably between 0 ° and the boiling point of the ketone used. The latter is preferably acetone, while the halogen-substituted methane derivative is preferably chloroform, and the compound of the formula XI preferably l, l, l-trichloro-2-methyl-2-propanol and, as a strong base, an alkali metal hydroxide, such as sodium or potassium hydroxide, comes into consideration. Since in the presence of these strong bases acetone and other methyl ketones are known to react with chloroform such as also with other tri- and tetrahalomethanes, such as brornoform, Carbon tetrachloride and carbon tetrabromide convert to compounds of the general formula XI, plays out in both procedural variants eventually the same reaction.

109841/1978

As alkali and alkaline earth metal salts of carboxylic acids falling under the general formula I, there are, for example, their Sodium, potassium, lithium, magnesium and calcium salts in question. These salts are produced, for example, by adding them together .of acid and base in a suitable solvent such as methanol, ethanol or acetone-water. Arisen, Salts that are relatively sparingly soluble can be isolated by filtering off, while those that are easily soluble can be isolated by evaporating the solvent. Further salts which are relatively sparingly soluble in the solvent used can also be changed by double reaction of another Prepare the salt of the acid with the base or a suitable salt thereof.

The compounds of general formula I and the alkali and alkaline earth metal salts of the free ones falling under this formula As mentioned above, carboxylic acids are administered orally or parenterally. The daily doses range between

10984.1 / 1978.

- .27. ■ '

0.5-10 mg / kg for warm-blooded animals. Suitable unit dosage forms, such as Dragees, tablets, suppositories and capsules contain as active ingredients preferably 10-250 rag, e.g. 50 or 100 rag of a compound of the general formula I or an alkali or alkaline earth metal salt one of the general formula I encompassed free carboxylic acid.

Unit dose forms for oral use contain preferably between 10 and 90 $ of a compound of the general formula I. To produce them, the active ingredient is combined, for example, with solid, powdery! Carriers, such as lactose, Sucrose, sorbitol, mannitol; Starches, such as potato starch, corn starch or amylopectin, also larainaria powder or citrus pulp powder; Cellulose derivatives or gelatin, optionally with the addition of lubricants such as magnesium or calcium stearate or Polyethylene glycols, for tablets or for coated tablets. The dragde kernels are coated with concentrated ones, for example Sugar solutions, which e.g. may contain gum arabic, talc and / or titanium dioxide, or with a varnish that is in volatile organic solvents or solvent mixtures is dissolved. Dyes can be added to these coatings, e.g. to mark different doses of active ingredients.

All other oral dosage unit forms are also suitable Push-fit capsules made of gelatin and soft, closed capsules made of gelatin and a plasticizer such as glycerine. The push-fit capsules contain the active ingredient preferably as granules, e.g. mixed with fillers such as corn starch and / or lubricants such as talc

109841/1978

or magnesium stearate, and optionally stabilizers such as sodium metadisulfite (Na ₂ S ₂ O ₁ -) or ascorbic acid. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as liquid polyethylene glycols,

The following regulations are intended to explain the manufacture of tablets, coated tablets, suppositories and capsules in more detail:

a) 1000 g of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid or 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -dcdecanoic acid are mixed with 550 g of lactose and 292 g of potato starch, the mixture with an alcoholic solution of 8 g Gelatin moistened and granulated through a sieve. After drying, mix 60 g of potato starch, 60 g of talc and 10 g Magnesium stearate and 20 g of highly dispersed silicon dioxide are added and the mixture is pressed into 10,000 tablets, each weighing 200 mg and 100 mg active ingredient content, the "possibly with partial notches can be provided for finer adjustment of the dosage.

b) 100 g of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid or 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -

dodecanoic acid are mixed with 16 g of corn starch and 6 g of highly dispersed Silica mixed well. The mixture is mixed with a solution of 2 g of stearic acid, 6 g of ethyl cellulose and 6 g of stearin moistened in about 70 ml of isopropyl alcohol and passed through a sieve III (Ph.HeIv.V) granulated. The granulate is dried for about 14 hours and then passed through a H-IIIa sieve. Then will it mixed with 16 g corn starch, 16 g talc and 2 g magnesium stearate and pressed into 1000 dragee cores. These are made with a concentrated syrup of 2 g Lacca, 7.5 g Arabic

109841/1978

- '29 -

Gum, 0.15 g dye, 2 g fumed silica, 25 g talc and 53.35 g sugar coated and dried. The received Dragees each weigh 260 mg and each contain 100 mg of active ingredient.

c) To produce 1000 capsules with 75 mg active ingredient content each, 75 g of 2- (6,7,8,9-tetrahydro-dibenzöfuran-2-yloxy) -octansMure are mixed or 2- (6,7,8,9-tetrahydro-dibenzofuran-2-ylthio) -octanoic acid with 198.0 g of lactose, moisten the mixture uniformly with an aqueous solution of 20 g of gelatin and granulate it through a suitable sieve (e.g. Sieve III according to Ph.HeIv.V). The granulate is mixed with 10.0 g dried corn starch and 15.0 g talc and fill it evenly into 1000 hard gelatine capsules of size 1.

The following examples explain the preparation of the compounds of general formula I and salts thereof but are not intended to limit the scope of the invention in any way. The temperatures are given in degrees Celsius. The term mmol means millimole == 0.001 mol. When naming the compounds produced, alkyl radicals, which deviate from the normal, unbranched chain, identified by designations such as sec. ~, tertiary or iso-alkyl. If these designations are missing, the normal, unbranched remainder is always meant.

109841/1978

example 1

In a round bottom flask with a reflux condenser, dropping funnel, Potassium hydroxide drying tube, stirrer and gas inlet tube are added 4.0 g (21.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol a solution of 0.48 g (21.0 mmol) of sodium in 50 ml of abs. Ethanol under nitrogen. To the thus obtained solution of Sodium 6,7,8,9-tetrahydro-dibenzofuran-2-olate is added dropwise with stirring 4.98 g (21.0 mmol) of 2-bromo-heptane-murine-ethyl ester and reflux for 4 hours. 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 sulphate, the ethereal solution is evaporated a light yellow oil is obtained. The crude ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -heptanoate, which is still contaminated with 6,7,8,9-tetrahydro-dibenzofuran-2-ol, is purified by column chromatography (Neutral silica gel 0.05-0.2 mm Merck, solvent benzene). The benzene fractions containing the desired ester will be combined and evaporated. After drying in a high vacuum, the pure ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-ylo :: y) -heptanoate is obtained, a slightly yellowish oil,

23 °
n ^ ³ : 1.5248.

109841/1978

Analogously one obtains:

from 4.0 g (21.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 3.8 g (21.0 mmol) of 2-bromo-propionic acid ethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -propion aure-äthyles ter,

g η £ ^ϋ : 1.5408;

from 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 the 2 - (6,7,8,9-Tetrahydro-dibenzofuran-2-yloxy) -2-methyl-propionic acid · ethyl ester, n ^ ³ °: 1.5361;

from 3.76 g (20.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 4.18 g (20.0 mmol) of ethyl 2-bromopentanoate, methyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) pentanoate, n; °: 1.5324;

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

2O °
n £ ^U : 1.5320; .

from 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 2.6 g (10.0 mmol) of 2-bromo-heptanoic acid propyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -heptanoic acid propyl ester,

? 0 °
η £ ^υ : 1.5220;

108841/1978

from 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 2.37 g (10.0 mmol) ethyl 2-bromo-isoheptanoate the 2- ( 6,7,8,9-Tetrahydro-dibenzofuran-2-yloxy) -isoheptanoic acid ethyl ester, η £ ^υ : 1.5241;

from 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, 7,8,9-Tetrahydro-dibenzofuran-2-yloxy) -octanoic acid ethyl ester, n £ ^U : 1.5219 ;

from 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 2.79 g (10.0 mmol) ethyl 2-bromo-decanoate the 2- (6, 7,8,9-Tetrahydro-dibenzofuran-2-yloxy) -decanoic acid ethyl ester, n ^ ^ü : 1.5262;

from 3.0 g (16.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 4.91 g (16.0 mmol) of ethyl 2-bromo-dodecanoate, ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) dodecanoate,

22 °
n ~: 1.5133;

from 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-Tetrahydro-dibenzofuran-2-yloxy) -tetradecanoic acid ethyl ester,

20 °
n ^ ^u : 1.5098 ;

109841/1978

from 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 3.63 g (10.0 mmol) ethyl 2-bromohexadecanoate the 2- (6, 7,8,9-fetrahydro-dibenzofuran-2-yloxy) -hexadecanoic acid ethyl ester, η £ ^Ο °: 1.5062;

from 1.88 g (10.0 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 2.35 g (10.0 mmol) of a-bromo-cyclopentaneacetic acid ethyl ester a- (6,7,8,9-Tetrahydro-dibenzofuran-2-yloxy) -cyclopentaneacetic acid ethyl ester, n ^ °: 1.5423;

from 1.88 g (10.0 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 2.49 g (10.0 mmol) of ethyl ct-bromo-cyclohexaneacetate α- (6,7,8,9-Tetrahydro-dibenzofuran-2-yloxy) -cyclohexanessigsäureäthylester, n ^ °; 1.5422;

from 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 1.95 g (10.0 mmol) ethyl 2-bromo-butyrate Ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -butyrate, n £ °°: 1.5372.

109841/1978

The 6,7,8,9-tetrahydrodibenzofuran-2-ol used as the starting material can be produced as follows:

a) 36.7 g (0.25 mol) of the sodium salt are placed in a three-necked round-bottomed flask equipped with a thermometer, stirrer and reflux condenser of the hydroquinone monomethyl ether in portions in. a solution of 46.6 g (0.264 mol) of 2-bromo-cyclohexanone registered in 130 ml of absolute toluene, the temperature rising from 25 ° to 50 °. The yellow one thus obtained Slurry is now heated under reflux for 2 hours, the sodium salt of hydroquinone monomethyl ether gradually dissolves and at the same time sodium bromide precipitates. After cooling, it is taken up in 700 ml of ether and Wash the essential solution four times with a total of 200 ml of 15% potassium hydroxide solution and water, dry over magnesium sulfate and steams in a vacuum. This gives 2- (4-methoxyphenoxy) cyclohexanone as a yellow oil. To twice recrystallization from ether-hexane gives pure 2- (4-methoxyphenoxy) cyclohexanone in the form of pale yellow needles with a melting point of 77-79 °.

10984Ϊ / Τ978

b) In a round bottom flask equipped with a stirrer, 4.0 g (18.0 mmoles) 2- (4-Methoxyphenoxy) cyclohexanone added in portions to 40 ml of phosphoric acid (d = 1.71), a grline Solution is formed, which is then heated to 105 ° for 2 1/2 hours. The color of the solution changes from grlin to red-brown, and at the same time an almost colorless oil is deposited. After cooling, you pour the reaction mixture on ice and extracted twice with a total of 200 ml of ether. The essential solution is washed off with 1-n. Caustic soda and water, dry them over magnesium sulfate and evaporate them in a vacuum. The 2-methoxy-6,7,8,9-tetrahydro-dibenzofuran is obtained as a brown oil, which is distilled twice in a bulb tube at 0.005 Torr between 80-100 °. The pure 2-methoxy-6,7,8,9-tetrahydro-dibenzofuran thus obtained is a colorless oil,

20 °
n £ ^u : 1.5783 *

c) In a round bottom flask with reflux condenser and potassium hydroxide drying tube, 3.0 g (14.85 mmol) of 2-methoxy-6,7,8,9-tetrahydro-dibenzofuran are mixed with 20.0 g of pyridine hydrochloride for 2 3/4 hours heated to 170 °. Then the still hot reaction mixture is poured onto a mixture of 200 g of ice and 100 ml of 1N hydrochloric acid and stirred for a further 1/2 hour.

109841/1978

The 6,7,8,9-tetrahydrodibenzofuran-2-ol which precipitates in white crystals is sucked off and washed with cold water until the washing water is neutral. After drying pure 6,7,8,9-tetrahydrodibenzofuian-2-ol is obtained in a high vacuum as a white powder, m.p. 106-107 °.

109841/1978

Example 2

In a round bottom flask with a reflux condenser, dropping funnel, Potassium hydroxide drying tube, stirrer and gas inlet tube 3.76 g (20.0 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-3-ol are added to a solution of 0.46 g (20.0 mmol) of sodium in 80 ml of absolute ethanol under nitrogen. To the thus obtained A solution of the sodium 6,7,8,9-tetrahydro-diben2ofuran-3-olate is added dropwise while stirring with 5.02 g (20.0 mmol) of ethyl 2-bromo-octanoate and reflux for 3 hours. After cooling, the reaction mixture is evaporated in vacuo and distribute the residue between water and ether. The ether phase is separated off and, after washing, it is also evaporated Water to pH = 7 and drying with magnesium sulfate in vacuo, a light yellow oil being obtained. The raw 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, benzene solvent). The benzene fractions containing the desired ester are combined and evaporated. Obtained after drying in a high vacuum the pure ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) octanoate, a slightly yellowish oil: 1.5233.

109841/1978

Analogously one obtains:

from 2.82 g (15.0 mol) 6,7,8,9-tetrahydro-diben2ofuran-3-ol and 2.8 g (15.0 mmol) ethyl 2-bromopropionate the 2- (6, 7,8,9-Tetrahydro-dibenzofüran-3-yloxy) propionic acid ethyl ester, n £ ^ü : 1.5426 ;

from 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 1.95 g (10.0 tmol) of 2-bromo-butyric acid-ethyl ester of 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -butters acid ethyl ester, n £ °: 1.5376;

from 2.82 g (15.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 2.92 g (15.0 mmol) ethyl 2-bromo-2-methyl-propionate .den 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-yloxy) -2-methyl-propionic acid, ethyl ester, n ^ ^u : 1.5366;

from 2.82 g (15.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 3.56 g of 2-bromo-isoheptane-acid ethyl ester 2- (6,7,8,9-Tetrahyaro

20 ° dibenzofuran-3-yloxy) -isoheptanoic acid ethyl ester, η: 1.5260;

from 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-ylöiiy) -dodecanoic acid ethyl ester, η ^ ^υ 1.5155;

109841/1978

from 2.82 g (15.0 mmoles) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 5.45 g (15, OmMoI) ethyl 2-bromo-hexadecanoate, ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) hexadecanoate,

np °°: 1.5075;

from 3.76 g (20.0 mmoles) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 4.99 g (20.0 mmol) of a-bromo-cyclohexaneacetic acid ethyl ester α- (6,7,8,9-Tetrahydro-dibenzofuran-3-yloxy) -cyclohexaneacetic acid ~ ethyl ester, η: 1.5445.

The 6,7,8,9-tetrahydro-dibenzofuran-3-ol used as starting material can be produced as follows:

a) In a three-necked round bottom flask with thermometer, stirrer and reflux condenser 300.0 g (2.05 mol) of the sodium salt of resorcinol monomethyl ether are added in portions to a solution of 382.0 g (2.16 mol) of 2-bromo-cyclohexanone in 825 ml of absolute Entered toluene, the temperature rising from 25 ° to 60 °. The yellow paste obtained in this way is then refluxed for 2 hours heated, whereby the sodium salt of resorcinol monomethyl ether gradually dissolves and at the same time sodium bromide precipitates. After cooling, the reaction mixture is distributed between ether and water, separates the ether phase and washes it four times with a total of 2.0 1 15% potassium hydroxide solution and water, dry them over magnesium sulphate and evaporate them in a vacuum.

109841/1978

The crude 2- (3-methoxyphenoxy; cyclohexanone) is obtained in this way as a yellow OeI. After recrystallizing twice from ether-hexane, pure 2- (3-methoxyphenoxy) cyclohexanone is obtained in the form of pale yellow crystals with a melting point of 72.5-73 °. The mother liquors which do not crystallize can also are further processed according to b).

b) 134.0 g (0.61 mol) of 2- (3-methoxyphenoxy) cyclohexanone are added in portions to 1340 ml of phosphoric acid (d = 1.71) in a round bottom flask with a stirrer, a green solution being formed which is then heated to 105 ° for 2 hours. After cooling, the reaction mixture is poured onto ice and extracted with ether. Wash the ethereal solution with 1N sodium hydroxide solution and water, dry it over magnesium sulphate and evaporate it 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 at 0.005 torr between 99-108 °. In this way, a colorless oil is obtained which, in addition to 3-methoxy-6,7,8,9-tetrahydro-dibenzofuran, according to the NMR spectrum contains about %% 1-methoxy-6,7,8,9-tetrahydro-dibenzofuran and is processed further without further purification.

1098 * 1/1978 ₀ «G. _N At, nspeoted

c) In a round bottom flask equipped with a reflux condenser and a potassium hydroxide drying tube 129.1 g (0.64 mol) of a mixture of 3- and 1-methoxy-6,7,8,9-tetrahydro-dibenzofuran obtained according to b) 2 3/4 hours with stirring with 401.1 g of pyridine hydrochloride. heated to 170 °. Then it will be the still hot reaction mixture poured onto a mixture of 800 g of ice and 400 ml of 1N hydrochloric acid and still Stirred for 1/2 hour. The precipitated oil is extracted with ether and the ethereal solution is concentrated, the crude 6,7,8,9-tetrahydro-dibenzofuran-3-ol with cooling crystallized. It is filtered off with suction and crystallized twice more from ether-gasoline. You get so pure 6,7,8,9-tetrahydro-dibenzofuran-3-ol in the form of light yellow crystals with a melting point of 105-106 °, while the 6,7,8,9-tetrahydro-dibenzofuran-1-ol Remains in the mother liquors.

109841/1978

Example 3

In a round bottom flask with a reflux condenser *, dropping funnel, Potassium hydroxide drying tube, stirrer and gas inlet tube adds 1.0 g (4.9 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-2-thiol to a solution of 0.112 g (4.9 mmol) of sodium in 10 ml of abs-ethanol under nitrogen.

To the thus obtained solution of the sodium-6,7,8,9-tetrahydro-dibenzofurane-2-thiolate is added dropwise 2-bromo-octansäureäthylester with stirring 1.23 g (4.9 mmol) and boiled for 3 hours under reflux, wherein nitrogen is constantly passed through the solution. After cooling, the reaction mixture is evaporated in vacuo and the residue is partitioned between water and ether. After washing with water to pH = 7 and drying with magnesium sulphate, the ethereal solution is evaporated to give a yellow oil. The crude ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-ylthio) -octanoate, which is still contaminated with 6,7,8,9-tetrahydro-dibenzofuran-2-thiol, is purified Column chromatography (neutral silica gel 0.05-0.2 mm, Merck, benzene solvent). The benzene fractions containing the desired ester are combined and evaporated. After drying in a high vacuum, the pure ethyl 2- (6,7,8,9-tetrahydro-dibenzofurcn-2-ylthio) octanoate, a colorless oil, is obtained

20 °
n £ ^u : 1.5465.

109841/1978

Analogously one obtains:

from 1.43 g (7.0 nmol) 6,7,8,9-tetrahydro-dibenzofuran-2-thiol and 1.27 g (7.0 ioMol) 2-bromopropionic acid ethyl ester 2- (6, 7,8,9-Tetrahydro-dibenzofuran-2-ylthio) -propionic acid ethyl ester, n £ ^ü : 1.5699, ·

from 2.0 g (9.78 mmol) 6,7,8,9-tetrahydro-dibenzofurane-2-thiol and 1.92 g (9.78 mmol) 2-bromo-2-methyl-propionic acid ethyl ester the 2 - (6.7, S ^ -Tetrahydro-dlbenzofuran ^ -ylthd ^ - ^ - methyl-propionic acid ^{ethyl ester, η ^ υ} : 1.5663;

from 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 £ ^u : 1,5503, · .. "

from 0.7 g (3.42 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-thiol and 1.24 g (3.42 mmol) of 2-bromo-hexadecanoic acid ethyl ester, 2- (6,7,8,9-tetrahydro-dibenzo £ uran-2-ylthio) -hexadecanoic acid ethyl ester,

20 °
tip: 1.5245.

109841/1978

ORiGJNAL INSPECTED

The 6,7,8,9-tetrahydrodibenzofuran-2-thiol used as the starting material can be made as follows:

a) In a round bottom flask with reflux condenser, stirrer, potassium hydro: ci d drying tube, Thermometer and gas inlet tube are added in small portions 0.48 g (10.0 mmol) of 50% sodium hydride - dispersion to a solution of 1.88 g (10.0 inMol) 6,7,8,9-tetrahydro-dibenzpfuran-2-ol in 10 ml of dimethylformamide under nitrogen. After 1/2 hour there is evolution of hydrogen completed. The resulting dark brown suspension is then cooled to 10 ° and then 1.65 g (13.0 mmol) of dirne thy lthiocarbamic acid chloride admitted at once. The temperature rises immediately to 18 °. Then there will be heated to 80 ° for one hour with stirring, sodium chloride precipitating in the solution, which is now light brown in color. N-? Ch After cooling, it is evaporated in vacuo and the remaining brown oil is distributed between ether and water. Man washes the ether phase several times with cold, dilute sodium hydroxide solution and water, dry over magnesium sulfate and evaporate they one, the crude dimethylthiocarbamic acid O- (6,7,8,9-tetrahydro-dibenzofuran-2-yl) ester remains as a yellow-brown oil which is determined by column chromatography [silica gel 0.05-0.2 mm, Merck, solvent benzene-ethyl acetate (9: 1)] is purified. "After evaporation of the pure fractions are this uinkristallisiert twice from aqueous methanol with the addition of activated charcoal. Mr-η thus gets the pure

1098A1 / 1978

Dimethylthiocarbamic acid O- (6,7,8,9-tetrahydro-dibenzofuran-2-yl) ester from m.p. 129-131 °.

b) In one equipped with a magnetic valve and a gas inlet pipe 9.6 g (35 mmol) of dimethylthiocarbamic acid 0- (6,7,8,9-tetrahydro-dibenzofuran-2-yl) ester are obtained from round-bottom flasks Heated for 3 1/2 hours at 280-295 ° under nitrogen and stirring. That so resulting dark brown OeI can be processed further directly after c) will. If necessary, it is purified by column chromatography [Silica gel 0.05-0.2 mm, Merck, solvent benzene-ethyl acetate (9: 1)]. The pure fractions are combined and evaporated. After recrystallizing twice from aqueous methanol, the pure dimethylthio- • carbamic acid S- (6,7,8,9-tetrahydro-dibenzofuran-2-yl) ester of m.p. 73-74 °.

c) In a round bottom flask equipped with a reflux condenser, stirrer, potassium hydroxide drying tube and gas inlet tube, a Solution of 3.0 g (11.0 mmol) of dimethylthiocarbamic acid S- (6,7,8,9-tetrahydro-dibenzofuran-2-yl) ester (Crude product) in 18.8 ml of 10% sodium hydroxide solution and 60 ml of methanol 3 1/2 Boiled for hours under nitrogen and reflux. After cooling, the methanol is evaporated off in vacuo, the residue acidified with 2N hydrochloric acid and extracted with ether. After washing the essential solution with water until pH * 7 and drying over magnesium sulfate is again

1 0984 1/1978

evaporated. The crude 6,7,8,9-tetrahydro-dibenzofuran-2-thiol is obtained as a yellow oil, which by column chromatography [silica gel 0.05-0.2 mm, Merck, solvent benzene-ethyl acetate (9: 1)] is cleaned. The pure fractions are combined and evaporated. After recrystallization from aqueous ethanol the 6,7,8,9-tetrahydro-cibenzofuran-2-thiol is obtained in the form pale yellow crystals, m.p. 44.5-46 °.

109841/1978

-. 47 -

Example 4

In a round bottom flask with a reflux condenser, dropping funnel, Potassium hydroxide drying tube, stirrer and gas inlet tube are added 4.08 g (20 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-3-thiol to a solution of 0.46 g (20 mmol) of sodium in 100 ml of abs. Ethanol under nitrogen.

To the solution of sodium 6,7,8,9-tetrahydro-dibenzofuran-3-thiolate thus obtained 5.02 g (20 mmol) of ethyl 2-bromo-octanoate are added dropwise, while stirring, and the mixture is boiled for 3 hours under reflux, with nitrogen being constantly bubbled through the solution. After cooling, the reaction mixture is evaporated in vacuo and the residue is partitioned between Water and ether. After washing with water until pH =? and Drying with magnesium sulfate, the ethereal solution is evaporated. The obtained, crude (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) octane ethyl ester, the one with 6,7,8,9-tetrahydro-dibenzofuran-3-thiol is contaminated, it is purified by column chromatography (neutral silica gel 0.05-0.2 mm, Merck, benzene solvent). The benzene fractions containing the desired ester are combined and evaporated. After drying in a high vacuum, the pure ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) octane acid is obtained, a yellowish oil, n ^: 1.5517.

108841/1976

Analogously one gets

from 2.04 g (10.0 mmoles) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 1.81 g (10.0 µmol) of 2-bromopropionic acid a'thyl ester the 2-

(6,7,8,9-Tetrahydro-dibenzofuran-3-ylthio) -propionic acid-ethyl-

20 °
ester, n_: 1.5768;

from 3.06 g (15 mmol) 6,7,8,9-Tetrahydro-dibenzoEuran-3-thiol and 4.6 g (15 mmol) of ethyl 2-bromo-dodecanoate, ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) dodecanoate,

2ο °
η £ ^υ : 1.5392;

from 1.7 g (8.35 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 3.03 g (8.35 mmol) methyl 2-bromo-hexadecanoate methyl ester 2- (6.7 , 8,9-Tetrahydro-dibenzof uran-3-ylthio) -hexadecsn acid-ethy ester,

20 °
n £ ^U : 1.5296; ·.

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

109841/1978

.- 49 -

The 6,7,8,9-tetrahydro used as starting material dibenzofuran-3-thiol can be made as follows:

a) Analogously to Example 3 a) one obtains

from 22.6 g (0.12 mol) 6 ^, S.g-Tetrahydro-dibenzofuran-S-ol and 19.8 g (0.16 moles) of dimethylthiocarbamine mure chloride Dimethylthiocarbamic acid O- (6,7,8,9-tetrahydro-dibenzofuran-3-yl) ester, Srnp. 158-159 ° (from ethyl acetate).

b) Analogously to Example 3 b) one obtains

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

c) Analogously to example 3 c) one obtains

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

109841/1978

To a solution of 0.23 g (10.0 mmol) of sodium in 23 ml Section. 2.043 g (10.0 mmoles) of 6,7,8,9-tetrahydrodibenzothiophen-2-ol are added to ethanol. While passing in nitrogen, 2.51 g (10.0 mmol) of ethyl 2-bromo-octanoate are added dropwise to the solution and heated the reaction mixture under reflux for 2 hours. After cooling, the ethanol is evaporated off in vacuo and the residue is distributed between water and ether. The ether extract, washed neutral with water, is dried over sodium sulfate and evaporated it in a vacuum. The crude product is purified by column chromatography on silica gel 0.05-0.2 mm, Merck, elution with benzene. The 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -octanoic acid is obtained

20 °

ethyl ester in the form of a colorless oil, η _β : 1.5498.

[With benzene / ethyl acetate (9: 1) there is still little starting phenol

'«
eluted].

Analogously one obtains:

from 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-dibenzothiophen-2-yloxy) -dodecanoic acid ethyl ester, η * ^υ : 1.5323;

109841/1978

enzothiophene

from 2.5Og (12.24 nvMol) ö ^ .S ^ -Tetrahj'dro-dibenzothiopi 2-ol and 4.45 g (12.2 mmol) of ethyl 2-bromo-hexadecanoate the 2- (6,7,8,9 '~ tetrahydro-dibenzothiophen-2-yloxy) -hexadecane

20 °
acid ethyl ester, η: 1.5271;

from 2.50 g (12.24 πίΜοΙ) 6,7,8,9-tetrahydro-dibenzothiophen ~ 2-ol and 2.21 g (12.2 mmol) of ethyl 2-bromopropionate, ethyl 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) propionate, Srap. 71-72 ° (from hexane);

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

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

1 09841/1978

2113 * 55

The 6,7,8,9-tetrahydrodibenzothiophen-2-ol used as the starting material can be made as follows:

a) 12 g (50.78 mmoles) of 2- (p-methoxyphenylthio) cyclohexanone are added to 120 ml of concentrated phosphoric acid (d = 1.71) with stirring and introduction of nitrogen. The reaction mixture is heated to 85 ° and it is stirred at this temperature for 14 hours. After cooling to room temperature it is poured onto ice and extracted with ether. The combined ether phases are with 2N sodium hydroxide solution and Washed water, dried over sodium and evaporated in vacuo. The purification of the resulting crystalline The crude product is carried out by column chromatography on silica gel 0.05-0.2 mm, Merck, eluent benzene-hexane [3: 2],

This gives pure 2-methoxy-6,7,8,9-tetrahydro-dibenzothiophene, M.p ... 85 ° (from hexane).

b) 3.5 g (16.03 mmol) of 2-methoxy-6,7,8,9-tetrahydro-dibenzothiophene are mixed with 28g (0.24 mol) of molten pyridine hydrochloride offset. The reaction mixture, which is under nitrogen, is stirred for 2 hours at 160-165 ° and distributed after cooling between 2N hydrochloric acid and ether. The combined ether extracts are washed neutral, over Dried sodium sulfate and evaporated in vacuo. That

109841/1978

Crude product obtained in crystalline form is purified by column chromatography on silica gel 0.02-0.5 mm, Merck. [elution with benzene and benzene-ethyl acetate (9: 1)]. Who wanted that Product-containing fractions are evaporated and recrystallized from methylene chloride-hexane. The received 6,7,8,9-Tetrahydro-dibenzothiophen-2-ol melts at 113-114 °.

109841/1978

Example 6

Analogous to example 5 one obtains:

from 4.08 g (20.0 m mol) 6,7,8,9-tetrahydro-dibenzothiophen-3-ol and 5.02 g (20.0 m mol) 2-bromo-octanoic acid ethyl ester 2- ( 6,7, 8,9-tetrahydro-dibenzothiophene-3-yloxy) -octanoic acid ethyl _ester: n _{D ^20:} 1.5482;

from 2.04 g (10.0 m mol) of e ^ .e ^ -Tetrahydro-dibenzothiophene-S-ol and 1.81 g (10.0 in mol) of ethyl 2-bromopropionate 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) propionic acid " ethyl ester, m.p. 41-43 ° (from hexane);

from 1.02 g (5.0 m mol) of e ^ S ^ -Tetrahydro-dibenzothiophen-O-ol and 1.82 g (5.0 mol) of ethyl Z-bromo-hexadecanoate

the 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) -hexadecanoic acid ethyl ester, M.p. 34-37 ° (from hexane);

from 2.04 g (10.0 m mol) 6,7,8,9-tetrahydro-dibenzothiophen-3-ol and 1.95 g (10.0 mol) of ethyl 2-bromo-2-methyl-propionate the 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 made as follows:

a) To a solution of 23.0 g (1.0 mol) of sodium in 700 ml of abs. Ethanol is added while stirring and passing in stick "τ ^Ρί: 140.2 g (1.0 mol) of m-methoxy-thiophenol

109841/1978

Then 177.0 g (1.0 mol) of 2-brorocyclohexanone are added dropwise in minutes, during which the reaction mixture warms up. It is then refluxed for a further 1.1 / 2 hours. The ethanol is then evaporated off in vacuo and the residue is partitioned between water and ether. The ether extract, washed neutral with water and dried over sodium sulfate, is evaporated. For purification, the crude product is fractionated in a high vacuum (20 cm Vigreux column). The 2- (m-methoxypheny1thio} -cyclohexanone with a boiling point of 146-147 ° / 0.15 Torr is obtained in the form of a yellow-colored oil, n _D : 1.5786;

b) 118.5 g (0.5 mol) of 2- [m-methoxyphenylthio] cyclohexanone are added to 1200 ml of concentrated phosphoric acid (d = 1.71) with stirring and introduction of nitrogen.

ϊ
The reaction mixture is heated to 105 ° and stirred for 5 hours at this temperature. After cooling to room temperature, it is poured onto ice and extracted with ether. The combined ether phases are with 2-n. Washed sodium hydroxide solution 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-The 3-methoxy-6,7,8,9-tetrahydro- dibenzothiophene with a melting point of 46 ° -46.5 ° (from methanol).

As a by-product, l-methoxy-6,7,8,9-tetrahydrodibenzothiophene, Snip. 57-58 ° (from methanol) isolated.

109841/1978

ORIGINAL INSPECTED

c) 54.57 g (0.25 mol) of 3-methoxy-6,7,8,9-tetrahydro-dibenzothiophene are freshly distilled with stirring and introduction of nitrogen to a melt of 150 g (0.77 mol) Given pyridine hydrochloride. The mixture is heated to 220 ° for 1.25 hours and the melt is then mixed into a mixture of 400 ml of 2N hydrochloric acid and 200 g of ice. After extraction with Aethef methylene chloride (3: 1) and washing the organic phase with water, drying over sodium sulfate and evaporation in vacuo resulting crystalline crude product is over silica gel [Merck, 0.05-0.2 mm, Elutiori with benzene-ethyl acetate (9: 1)] filtered and recrystallized from methylene chloride-hexane. The 6,7,8,9-tetrahydro-dibenzothiophen-3-ol is obtained of m.p. 117-118 ° (from methanol).

109841/1978

Example 7

To 'a solution of 0.11 g (4.78 mmol) of sodium in 20 ml of abs. Ethanol is added 1.0 g (4.54 mmol) of 6,7,8,9-tetrahydrofuran-dibenzothiophene-2-thiol. 0.86 g (4.78 mmol) of ethyl 2-bromopropionate are rapidly added dropwise to this solution while stirring and passing in nitrogen. The reaction mixture is boiled under reflux for 3 hours. After cooling, the ethanol is evaporated off in vacuo and the residue is partitioned between water and ether. The ether extract, washed neutral with water and dried over sodium sulfate, is evaporated in vacuo and the yellow-colored oil that remains is purified by column chromatography on Merck silica gel, eluting with benzene-hexane (2: 1). The ethyl 2- (6,7,8,9-tetrahydrodibenzothiophen-2-ylthio) propionate is obtained in the form of a colorless oil, n ^ ^u : 1.6023.

'i

Analogously one obtains:

from 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, n ^ ⁰ °: 1.5728;

from 1.0 g (4.54 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 1.47 g (4.80 mmol) ethyl 2-bromo-dodecanoate the 2- (6, 7,8,9-tetrahydro-dibenzothiophen-2-ylthio) -dodecan-

Of) "

acid ethy ester, n ^ ^u : 1.5561;

108841/1978

from 1.0 g (4.54 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 1.73 g (4.78 mmol) of ethyl 2-bromo-hexadecanoate 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) -hexadecane

2n °
acid ethyl ester, n ^: 1.5439;

from 1.0 g (4.54 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 0.94 g (4.82 mmol) ethyl 2-bromo-2-methyl-propionate the 2- (6,7,8,9-tetrahydro-dibenzothiophen-2 ~ ylthio) 2-methyl-propionic acid ethyl ester.

109841 / 1Sf8

The 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol used as the starting material can be made as follows:

a) To the solution of 10.0 g (49.0 mmol) cooled to approx. 5 ° 6,7,8,9-tetrahydro-dibenzothiophen-2-ol in 50 ml abs. Dimethylformamide is added in portions with stirring and introduction of nitrogen 2.35 g (49.0 mmol) of 50% sodium hydride dispersion. After stirring for 1/2 hour at room temperature and 5 minutes at 80 °, the evolution of hydrogen ceased completed. Now 8.07 g (65.4 mmol) of dimethylthiocarbamic acid chloride are added at 5-10 ° in 10 ml abs. Dimethylformamide was added dropwise within about 2 minutes and the reaction mixture Stirred for another 2 hours at 80 °. After cooling, it is evaporated in vacuo, the residue is taken up in water and extract it thoroughly with ether and chloroform. The combined organic phases are washed with water, dried over magnesium sulfate, evaporated and the residue by column chromatography on silica gel 0.05-0.2 mm, Merck, elution with benzene / ethyl acetate [9: 1].

The dimethylthiocarbamic acid O-iö ^ .S.g-tetrahydro-dibenzothiophen-2-yl) ester is obtained from m.p. 154-155 °. (Methanol or ethyl acetate).

109841/1978

b) In a nitrogen atmosphere, 9.0 g (30.9 mmol) Dirnethylthiocarbamic acid-0- (6,7, S ^ -tetrahydro-dibenzothiophene ^ -yl) -ester brought to melt at 230 ° and then heated for 3 minutes at 350 °. After cooling down The yellow-colored residue is purified (by means of a stream of air) by column chromatography on Merck silica gel (Elution with benzene-ethyl acetate (19: 1)] - The fractions containing the desired product are combined and removed Recrystallized methanol. Dimethylthiocarbamic acid S- (6,7,8,9-tetrahydro-dibenzothiophen ~ 2-yl) ~ is obtained in this way ester of m.p. 98-99 ° (from methanol).

c) With stirring and introduction of nitrogen v / earth 5.1 g (17.5 mmol) dimethylthiocarbamic acid S- (6,7,8,9-tetrahydro-dibenzothiophen-2-yl) ester boiled under reflux for 3 hours in 100 ml of methanol and 80 ml of 10X sodium hydroxide solution. The organic solvent is then evaporated in vacuo, the residue acidified with 1N hydrochloric acid and with ether extracted. The washed with water and over magnesium sulfate The dried ether phase is evaporated in vacuo and the residue is chromatographed on silica gel, Merck, elution with benzene and benzene-ethyl acetate (19: 1). This is obtained after recrystallization from methylene chloride-hexane 6.7 »8,9-tetrahydro-dibenzothiophene-2-thiol of m.p. 64-65 °.

109841/1978

Example 8

Analogous to example 7 one obtains:

from 1.30 g (5.9OmMoI) 6,7,8,9-tetrahydro-dibenzothiophene-3-thiol and 1.48 g (5.90 mmol) of 2-bromo-octanoic acid ethyl ester 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio) -octanoic acid-

20th

ethyl ester, n _D : 1.5754;

from 2.20 g (10.0 mmol) 6.7, e 1-tetrahydro-dibenzothiophene-S-thiol and 3.07 g (10.0 mmol) of ethyl 2-bromo-dodecanoate, 3.70 g of 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio) -

20 °
ethyl dodecanoate, n _ß : 1.5594;

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

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

109841/1978

The 6,7,8,9-tetrahydrodibenzothiophene-3-thiol used as the starting material can be prepared analogously to the reaction sequence described in Example 7a), b) and c):

a) Analogously to Example 7 a), 16.0 g (78.3 mmol) are obtained 6,7,8,9-tetrahydro-dibenzothiophen-3-ol and 12.95 g (104.9 mmol ·) Dimethylthiocarbamic acid chloride the dimethylthiocarbamic acid O- (6,7,8,9-tetrahydro-dibenzothiophen-3-yl) ester of m.p. 139.5-140 ° (from methanol).

b) As in Example 7 b), but at one reaction temperature of 260 ° and a reaction time of 5 hours, 12.10 g (41.5 mmol) of dimethylthiocarbamic acid O- (6,7,8,9-tetrahydro-dibenzothiophen-3-yl) ester are obtained the dimethylthiocarbamic acid S- (6,7,8,9-tetrahydro-dibenzothiophen-3-yi) - ester of m.p. 98-99 ° (from methanol).

c) Analogously to Example 7 c), 8.74 g (30.0 mmol) of dimethyl thiocarbamic acid S- (6,7,8,9-tetrahydro-dibenzothiophen-3-yl) ester are obtained the 6,7,8,9-tetrahydro-dibenzothiophene-3-thiol of m.p. 36-36.5 ° (from hexane).

109841/1978

In a round bottom flask with a reflux condenser, dropping funnel, Potassium hydroxide drying tube, stirrer and gas inlet tube are added

2.82 g (15 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-2-ol are added a solution of 0.345 g (15 mmol) of sodium in 25 ml of abs. Ethanol under nitrogen. To the solution thus obtained of the sodium 6,7,8,9-tetrahydro-dibenzofuran-2-olate is added dropwise with stirring an ethanolic solution prepared in the same way Solution of the sodium salt of 2-bromo-heptanoic acid [from 3.14 g (15 mmol) 2-bromo-hentanoic acid, 0.345 g (15 mmol) sodium, 60 ml absolute ethanol] and reflux for 8 hours. To the cooling, the reaction mixture is evaporated in vacuo, the residue that remains is suspended in water and with concentrated hydrochloric acid acidified. The thereby failing OeI becomes taken up in aether. ' The essential solution is washed off

with water, dry with magnesium sulfate and steam that Solvent in vacuo. The crude 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -heptanoic acid remaining as oil, which mainly still with 6,7,8,9-tetrahydro-dibenzofuran-2-ol Is contaminated, is column chromatography on silica gel 0.05-0.2 mm, Merck, solvent benzene-glacial acetic acid (85:15) cleaned. The solid residue obtained after evaporation of the pure fractions is extracted twice Recrystallized methanol-water. The pure 2- (6, 7, 8, 9-tetrahydro-dibenzofuran-2-yloxy) -heptanoic acid is obtained in this way 123-124 °.

109841/1978

Analogously one obtains: £ M O 4 0 ρ

from 2.82 g (15 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol

and 2.30 g (15 mmol) of 2-bromopropionic acid, the 2- (6,7,8,? - Tetrahydro-dibenzofuran-2-yloxy) propionic acid of m.p. 128-129 ° (from methanol-water);

from 2.82 g (15 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 3.34 g (15 mmol) 2-bromo-octanoic acid the 2- (6,7,8,9- Tetrahydro-dibenzofuran-2-yloxy) -octanoic acid with a melting point of 99-100 ° (from methanol-water) ;

from 2.82 g (15 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 4.19 g (15 mmol) of 2-bromo-dodecanoic acid, 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -dodecanoic acid from m.p. 65-66 ° (from Pent, on);

from 2.82 g (15 mmol) 6.7, S 1-tetrahydro-dibenzofuran-S-ol and 3.35 g (15 mmol). 2-bromo-octanoic acid 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -octanoic acid of melting point 78-79 ° (from hexane) ;

109841/1978

from 2.82 g (15 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 4.19 g (15 mmol) 2-bromo-dodecanoic acid the 2- (6,7,8,9- Tetrahydrodibenzofuran-3-yloxy) dodecanoic acid of melting point 87-87.5 ° (from hexane) ;

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

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

from 6.12 g (30 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 8.37 g (30 mmol) 2-bromo-dodecanoic acid the 2- (6.7 _r 8.9- Tetrahydro · dibenzofwran-3-ylthio) dodecanoic acid with a melting point of 73.5 ° -74.5 ° (from hexane);

10984t / 1978

Example 10

To a solution of 2.3 g (100 mmol) sodium in 100 ml Section. Ethanol is added to 10.20 g '(50 mmol) of 6,7,8,9-tetrahydrodibenzothiophen-2-ol. A solution of 11.15 g (50 mmol) of 2-bromo-octanoic acid in 60 ml of abs-ethanol were quickly added dropwise. The reaction mixture is boiled 4 hours under reflux, it is then evaporated in vacuo and the residue is taken up in water. After acidification with conc. Hydrochloric acid is extracted with ether. The extract, washed neutral with water and dried over sodium, is evaporated in the Vacuum and clean the remaining, yellow colored oil by column chromatography on silica gel 0.05-0.2 mm, Merck, elution with benzene-ethyl acetate (9: 1) and benzene-glacial acetic acid (19: 1). After recrystallization of the pure fractions from hexane the 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -octansäure of m.p. 90-91 °.

Analogously one obtains:

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

from 11.0 g (50 mmol) o ^ jS.g
thiol and 10.45 g 50 mmol-2-bromo-heptanoic acid 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) -heptanoic acid with a melting point of 101 ° (from hexane);

109841/1978

from 11.0 g (50 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 11.15 g (50 mmol) 2-bromo-octanoic acid the 2- (6,7,8,9- Tetrahydro-dibenzothiophen-2 ~ ylthio) -octanoic acid of melting point 91-92 ^c (from hexane) ;

from 11.0 g (50 mmol) δ ^ .S ^ -Tetrahydro-dibenzothiophene-S-thiol and 11.15 g (50 mmol) of 2-bromo-octanoic acid, the 2- (6,7,8,9-

20 ° tetrahydro-dibenzothiophen-3-ylthio) octanoic acid, η: 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).

109841/1978

Betspiel 11

In a round bottom flask with reflux condenser, dropping funnel, potassium hydroxide drying tube, * stirrer and gas inlet tube are added 4.0 g (21 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-2-ol to a solution of O _r 48 g ( 21 mmol) sodium in 50 ml abs. Ethanol under nitrogen. A solution of 3.43 g (21 mmol) of 2-chloro-heptanamide in 50 ml of absolute ethanol and reflux for 6 hours. After cooling, the reaction mixture is evaporated in vacuo and the residue is partitioned 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 is crystallized twice from ethanol. This gives pure 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -

heptanamide of 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-dibenzofuran-2-yloxy) -octanamide of m.p. 130-131 °. (from ethanol-water);

109841/1978

from 4.0 g (21 mmol) 6,7,8,9-tetrahydro-dibenzo £ uran-2-oI and 2.25 g (21 mmol) 2-chloro-propionamide 2- (6,7,8, 9-tetrahydro-dibenzofuran-2-ylq _i xy) propionainide;

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

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

from 4.0 g (21 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 4.90 g (21 mmol) of 2-chloro-dodecanamide 2- (6,7, S.g-tetrahydrodibenzofuran-S-yliDxy ^ dodecanamide of melting point 131.5-132.5 ° (from ethyl acetate);

109841/1978

- 70 - - 2112455

from 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 of melting point 135-136 ° (from ethanol);

from 4.34 g (21 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 3.72 g (21 mmol) of 2-chloro-octanamide 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -octanamide of melting point 107.5-109 ° (from ethanol-water);

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

109841/1978

2112455

from 4.34 g (21 nmoles) 6,7,8,9-tetrahydro-dibenzothiophen-3-ol and 3.72 g (21 next) 2-chloro-octanamide 2- (6,7,8,9-tetrahydro-dibenzojthiophen-3-yloxy) -octanamide of m.p. 116-117 ° (from methanol);

from 4.68 g (21 nmoles) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 3.43 g (21 n * fol) 2-chloro-heptanamide 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) -heptanamide of m.p. 150-150.5 ° (from methanol);

from 4.68 g (21 next) 6,7,8, g-tetrahydro-dibenzothiophene-S-thiol and 3.72 g (21 ntfol) 2-chloro-octanaraid the 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio-octanamide.

100841/1978

Example 12

6.2 g (18 mmol) of ethyl 2- (6,7,8,9-tetrahydrodibenzofuran-2-yloxy) -heptanoate are placed in a round-bottom flask with a reflux condenser 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 Boiled under reflux. After cooling, the reaction mixture is evaporated in vacuo, and the residue is partitioned between dilute Hydrochloric acid and ether and ether out. The combined ethereal solutions are washed neutral with water over magnesium sulfate dried 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 M.p. 12-3-124 °.

2- (6,7,8,9-Tetrahydro-dibenzofuran-2-yloxy) -heptanoic acid is obtained analogously and in the same condition the 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -heptanoic acid methyl- or propyl ester.

Analogously one obtains

from 4.6 g (16 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) propionate 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) propionic acid, M.p. 128-129 ° (from methanol-water);

109841/1978

from 1.25 g (4 mol) of 2- (6, 7, 8,9-tetrahydro-diDenzüj.Ui: an-2-yloxy) -2-methyl-propionic acid ethyl ester 2- (6, 7,8,9-tetrahydro-dibenzofuran-2-yloxy) -2-methyl-propionic acid, M.p. 136.5-138 ° (from methanol-water);

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

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

from 11.6 g (35 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid-ethyls'ter the 2- (6,7, 8,9-tetrahydro-dibenzofuran 2-yloxy) octanoic acid, melting point 99-100 ° (from hexane);

from 2.3 g (6 mmol) 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -

ethyl decanoate 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) decanoic acid, M.p. 70-71 ° (from hexane;

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

108841/1978

from 2.5 g (6 mmoles) of ethyl 2- (6,7,8,9-tetrahydro-dibenzpfuran-2-yloxy) tetradecanoate 2- (6,7,8,9-tetrahydrodibenzofuran-2-yloxy) -tetradecanoic acid, m.p. 52.5-55 ° ' (from hexane);

from 2.8 g (6 nmoles) of ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) hexadecanoate 2- (6,7,8,9-tetrahydrodibenzofuran-2-yloxy) -hexadecanoic acid, m.p. 55-56 ° (from hexane);

from 1.0 g (3 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -cyclopentane acetic acid-ethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -cyclopentane acetic acid, M.p. 103-104 ° (from hexane);

from 1.7 g (5 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) cyclohexane acetic acid 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -cyclohexaneacetic acid, Mp 133-134 ° (from methanol-water);

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

109841/1978

Example 13

5.7 g (16 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofurane-3-yloxy) -octanoic acid-ether are placed in a round-bottom flask with a reflux condenser 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 boiled under reflux. After cooling down, it is steamed Reaction mixture in a vacuum, distribute the residue between dilute hydrochloric acid and ether and ether out. the combined ethereal solutions are washed neutral with water, dried over magnesium sulfate and evaporated again, the crude 2- (6,7,8,9-tetrahydro-dibenzofuran 3-yloxy) octanoic acid remains as a yellow oil. After two crystallizations from hexane, pure 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -octanoic acid is obtained in the form of pale yellow crystals of m.p. 78-79 °.

Analogously one obtains:

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

from 2.1 g (7 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) butyric acid 2- (6,7,8,9-tetrahydrodibenzofuran-3-yloxy) butyric acid, M.p. 106-107 ° (from hexane);

109841/1978

from 2.4 g (8 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -2-methyl-propionic acid 2- (6,7, 8,9-tetrahydrodibenzofuran-3-yloxy) -2-methyl-propionic acid, M.p. 78-80 ° (from hexane);

from 3.9 g (11.3 mmoles) of ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) isoheptanoate 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -isoheptanoic acid, melting point 104-105 ° (from hexane);

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

from 5.6 g (12.0 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -hexadecanoate 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -hexadecanoic acid, M.p. 77.5-78.5 ° (from methanol-water); "

from 2.8 g (7.8 mmol) of α- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -cyclohexane acetic acid - ethyl ester α- (6,7,8,9-tetrahydro-dibenzofuran-3-ylox ^ y) -cyclohexaneacetic acid, M.p. 118-120 ° (from hexane).

109841/1978

Example 14

Ground 1.4 g in a round bottom flask with a reflux condenser (3.73 mmoles) 2- (6,7,8,9-Tetrahydro-dibenzofuran-2-ylthio) -octanoic acid ethyl ester in a solution of 0.414 g (7.4 mmol) potassium hydroxide boiled under reflux for 5 1/2 hours in 20 ml of methanol and 1 ml of water. After cooling, the reaction mixture is evaporated in vacuo and the residue is partitioned between water and ether, acidify the aqueous phase with 2N hydrochloric acid and ethers it out. The united ethereal exercises are with Washed water until neutral, dried over magnesium sulfate and evaporated again. Crude 2- (6,7,8,9-tetrahydrodibenzofuran-2-ylthio) octanoic acid is obtained as a colorless oil. The pure 2- (6,7,8,9-tetrahydro-dibenzofuran-2-ylthio) -octanoic acid crystallizes from hexane. in the form of white crystals with a melting point of 92-93 °.

Analogously one obtains:

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

from 2.7 g (8.47 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-ylthio) -2-methyl-propionic acid 2- (6,7,8,9-tetrahydro-dibenzofuran-2-ylthio) -2-methyl-propionic acid, M.p. 146-147 ° (from ether-hexane);

109841/1978

from 2.1 g (5.8 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-ylthio) isoheptanoate 2- (6,7,8,9-Tetrahydrb-dibenzofuran-2-ylthio) -isoheptanoic acid, M.p. 71.5-73 ° (from hexane);

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

109841/1978

Example 15

In a round bottom flask with a reflux condenser, 6.35 g (17 mmol) ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) octanoate in a solution of 2.6 g (46 mmol) of potassium hydroxide in 60 ml of methanol and 6 ml of water under reflux for 4 hours cooked. After cooling, the reaction mixture is evaporated in vacuo, the oily residue is suspended in water, acidifies with dilute hydrochloric acid and ethers out several times. The ether extracts are washed neutral with water over magnesium sulfate dried and evaporated again. Crystallization of the oily residue from hexane gives 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) octanoic acid in the form of white crystals with a melting point of 62-63 °.

Analogously one obtains:

from 2.1 g (6.9 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) propionate 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) propionic acid, Mp 133-134 ° (from methanol-water);

from 5.45 g (12.7 mmol) 2- (6,7,8, g-Tetrahydro-dibenzofuran-S-ylthio) ethyl dodecanoate 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) dodecanoic acid, M.p. 73.5-74.5 ° (from hexane);

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

109841/1978

2113465

Example 16

To a solution of 2.1 g (5.607 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) octanoate a solution of 0.65 g (9.96 mmol) of potassium hydroxide (86%) in 5 ml of water is added to 25 ml of methanol. The mixture is boiled Reflux for 1 1/2 hours and evaporate it in vacuo. The residue is between dilute hydrochloric acid and ether distributed. The ether phase, washed neutral with water, is dried over sodium sulfate and evaporated in vacuo. After recrystallization of the crude product from methylene chloride-hexane, 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -octanoic acid is obtained, M.p. 90-91.

Analogously one obtains:
«

from 1.92 g (4.46 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophenes 2-yloxy) -. Dodecanoic acid ethyl ester 2- (6,7, 8,9-tetrahydrodibenzothiophen-2-yloxy) -dodecanoic acid, M.p. 74-76 ° (from methylene chloride-hexane); ·

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

109841/1978

from 1.76 g (5.53 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -2-methyl-propionic acid the 2- (6,7,8,9-tetra-

hydro-dibenzothiophen-2-yloxy) -2-methyl-propionic acid, m.p. 121-122 (from methylene chloride-hexane);

from 1.80 g (5.42 mmol) 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -3-methyl-butyric acid ethyl ester the 2- (6,7,8,9- Tetrahydrodibenzothiophen-2-yloxy) -3-methyl-butyric acid, melting point 91-93 ° (from methylene chloride-hexane) ;

from 1.94 g (3.99 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) hexadecanoate 2- (6,7,8,9-tetrahydro-dibenzothiophen ~ 2-yloxy) -hexadecanoic acid, M.p. 89-91 ° (from methanol).

109841/1978

Analogous to example 16 one obtains:

from 3.10 g (8.28 mi-Ιοί) 2- (6,7,8,9-tetrahydro-dibenzothiophene 3-yloxy) -octanoic acid ethyl ester 2- (6,7,8,9-tetrahydrodibenzothiophen-3-yloxy) -octanoic acid, M.p. 106-107 ° (hexane);

from 3.04 g (10.0 mmol) 2- (6.7, S ^ -Tetrahydro-dibenzothiophene S-yloxy ^ propionic acid ethyl ester the 2- (6,7,8,9-tetrahydrodibenzothiophen-3-yloxy) - propionic acid, m.p. 146-147 ° (hexane)

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

109841/1978

1.0 g (3.12 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) propionate are dissolved in 20 ml of methanol, 0.75 g of potassium hydroxide and 2 ml of water are added and refluxed for 1 1/2 hours while passing in nitrogen. After cooling, the reaction mixture is evaporated in a vacuum and partition the residue between dilute hydrochloric acid and ether. The ether phase is separated, washed neutral with water, dried over sodium sulfate and evaporated. The resulting crude acid is made from methylene chloride-hexane recrystallized. The 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) propionic acid is obtained, M.p. 106-107 °.

Analogously one obtains:

from 2.15 g (5.51 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) octanoate 2- (6,7T879 ^ dibenzothiophen- 2-ylthio) -octanoic acid, M.p. 91-92 ° (hexane);

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

from 1.92 g (3.83 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) hexadecanoate 2- (6,7,8,9-tetrahydrodibenzothiophen-2-ylthio) -hexadecanoic acid of m.p. 68-70 "(hexane), *

109841/1978

from 1.20 g (3.07 mmol) 2- (6,7,8,9-tetrahydro

-dibenzothiopnen-

3-ylthio) -octanoic acid ethyl ester the 2- (6,7,8,9-tetrahydro-

20 °
dibenzothiophen-3-ylthio) octanoic acid as OeI, η: 1.5848;

from 3.20 g (7.17 mmol ·) ethyl 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio) dodecanoate the 2- (6,7,8,9-tetrahydro-

20 °
dibenzothiophen-3-ylthio) dodecanoic acid as OeI, η: 1.5718;

The last two acids mentioned, which do not crystallize, can be purified by chromatography on silica gel Merck 0.05-0.2 mm eluting with benzene and benzene-glacial acetic acid (49: 1).

109841/1978

Example 19

In a round bottom flask with a reflux condenser, 3.15 g (10 mmol) 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -heptane ~ amide in a solution of 3 g (50 mmol) potassium hydroxide in 70 ml Ethanol and 7 ml of water boiled under reflux for 20 hours. After cooling, the reaction mixture is treated with 2-n. hydrochloric acid acidified, the ethanol evaporated in vacuo, the remaining aqueous phase extracted with ether and the ethereal solution twice washed with water. After drying with sodium sulfate, the ether phase is evaporated. The remaining, crude 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -heptanoic acid is recrystallized twice from methanol-water. M.p. of the pure acid 123-124 °.

Analogously one obtains:

from 3.28 g (10 mmoles) of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanamide 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid of m.p. 99-100 ° (from hexane);

from 3.44 g of 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -octanamide 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -octanoic acid of m.p. 62-63 ° (from hexane).

109841/1978

21134Ü5

Example 20

1.60 g (4.60 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) -heptanamide are dissolved in 40 ml of ethanol, mixed with a solution of 2.3 g (41 mmol) of potassium hydroxide in 40 ml of water and the reaction mixture was refluxed for 45 hours. After evaporation of the ethanol in vacuo, the residue is distributed between 1N hydrochloric acid and ether. The severed, with water washed and dried over sodium sulfate ether phase is evaporated and the crude product is omcrystallized from hexane. The 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) -heptane acid is obtained in this way of m.p. 101 °.

Analogously one obtains

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

from 1.38 g (4.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) -octanamide 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) -octanoic acid of m.p. 106-107 ° (from hexane).

109841/1978

Example 21

In a round bottom flask equipped with a reflux condenser and stirrer, 2.4 g (7 mmol) of 2 _r (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanamide in a mixture of 30 ml of 6N hydrochloric acid and 50 ml of glacial acetic acid refluxed for 5 hours. After cooling, the reaction mixture is evaporated in vacuo and the residue that remains is taken up in ether. The ethereal solution is first washed with water, then extracted with 2N sodium hydroxide solution, the alkaline extract is separated off and washed with ether.

The alkaline solution is then treated with concentrated hydrochloric acid acidified (pH = 1) and the resulting oil in ether recorded. The ethereal solution thus obtained is washed neutral with water, dried over magnesium sulfate and in vacuo evaporated, the crude 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid; as yellow OeI received. After recrystallizing twice from hexane, the pure acid is obtained in the form white crystals of m.p. 99-100 °.

109841/1978

Example 22

In a round bottom flask with a reflux condenser, 0.3 g (1 mmol) 2- (6, 7, 8,9-tetrahydro "-dibenzofuran-2-yloxy) -heptanoic acid nitrile in a solution of 0.3 g (5 mmol) of potassium hydroxide in 20 ml Ethanol and 2 ml of water boiled under reflux for 20 hours. After cooling, the reaction solution is acidified with 2N hydrochloric acid, the ethanol is evaporated in vacuo, the remaining aqueous phase is extracted with ether and the ether solution is washed twice with water. After drying with sodium sulfate, the ether phase is evaporated. The remaining, crude 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -heptanoic acid is recrystallized from methanol-water, the pure acid having a melting point of 123-124 ° is obtained.

Analogously one obtains

from 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 of m.p. 99-100 ° (from hexane).

from 3.12 g (10 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -octanoic acid nitrile 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -octanoic acid of melting point 78-79 ° (from hexane);

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

109841/1978

from 3.28 g (10 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -octanoic acid nitrile 2- (6,7,8,9-tetrahydroV3-ylthio) octanoic acid of m.p. 62-63 ° (from hexane).

The 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -heptanoic acid nitrile used as the starting material can be made as follows:

a) In a round bottom flask with reflux condenser, dropping funnel, potassium hydroxide drying tube, 3.76 g (20 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-2-ol are added to the stirrer and gas inlet tube a solution of 0.46 g (20 mmol) of sodium in 30 ml of absolute ethanol under nitrogen. To the solution of sodium 6,7,8,9-tetrahydro-dibenzofuran-2-olate thus obtained one drips under

Stir 3.8 g (20 mmol) of 2-bromo-heptanoic acid nitrile and boil 3 hours under reflux. 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 ethereal solution is evaporated, 6.0 g of a brown oil are obtained. The crude 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -heptanoic acid nitrile ,. which is still mainly contaminated with 6,7,8,9-tetrahydro-dibenzofuran-2-ol is purified by column chromatography (neutral silica gel 0.05-0.2 mm, Merck, benzene solvent). the

109841/1978

the benzene fractions containing the desired nitrile are combined and evaporated. Obtained after drying in a high vacuum

the pure 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -

20 °
heptanoic acid nitrile, a yellow oil, η: 1.5395.

Analogously one obtains

from 15.1 g (80 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol

and 16.32 g. (80 mmol) 2-bromo-octanoic acid nitrile 2- (6,7,8,9-

23 °

Tetrahydro-dibenzofuran-2-yloxy) octanoic acid nitrile, η; 1.5355

from 7.52 g (40 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-l and 8.16 g (40 mmol) of 2-bromo-octanoic acid nitrile 2- (6,7,8,9-

20 °

Tetrahydro-dibenzofuran-3-yloxy) octanoic acid nitrxl, η: 1.5366;

from 6.92 g (33.8 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-thiol and 6.9 g (33.8 mmol) of 2-bromo-octanoic acid nitrile. the 2- (6,7,8,9-tetrahydro-dibenzofuran-2-ylthio) -octansäurenitrxl, n ": 1.5645

from 4.08 g (20 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-3-Tmol and 4.1 g (20 mmol) of 2-bromo-octansäurenitril '2- (6,7,8,9 -Tetra-

20 °

hydro-dibenzofuran-3-ylthio) octanoic acid nitrile, n _ß : 1.5704.

109841/1978

Example 23

To 3.28 g (10 mmol) of 2- (6 »7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -octanoic acid Ltrile in 70 ml of ethanol a solution of 5.0 g (89 mmol) of potassium hydroxide in 15 ml of water is added and reflux the mixture for 24 hours. The ethanol is then evaporated off in vacuo, the residue with 2N hydrochloric acid acidified and extracted with ether. The extract, washed neutral with water and dried over sodium sulfate, is evaporated one in a vacuum. The remaining, crude hydrolysis product becomes recrystallized from hexane. 2- (6,7,8,9-Tetrahydro-dibenzothiophen-2-yloxy) -octanoic acid is obtained of m.p. 90-91 °.

Analogously one obtains

from 3.28 g (10.0 ^ 1ol) 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) -octanoic acid nitrile the 2- (6 _r 7,8,9-tetrahydro-dibenzothiophene-3 -yloxy) -octanoic acid with a melting point of 105-107 ° (from hexane);

from 3.30 g (10.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) -heptanoic acid nitrile 2- (6,7,8,9-tetrahydro-dibenzo thiophen-2-ylthio-heptanoic acid with a melting point of 101 ° (from hexane);

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

1098A1 / 1978

The 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -octanoic acid nitrile used as the starting material can be made as follows:

a) To a solution of 1.47 g (63.7 in mol) of sodium in 120 ml Absolute ethanol is added to 13.0 g (63.7 mmol) of 6,7,8,9-tetrahydro-dibenzothiophen-2-ol. While stirring and passing in nitrogen, 13.0 g (63.7 mmol ·) of 2-bromooctanoic acid nitrile are rapidly obtained added dropwise in 50 ml of absolute ethanol. The reaction mixture is refluxed for 5 hours and then evaporated in vacuo. The residue taken up in water is extracted with ether. The ether phase is washed neutral with water, dried over sodium sulfate and evaporated in vacuo. Chromatographed for purification. the crude product on silica gel, Merck 0.05

0.2 mm, elution with benzene-hexane (2: 1). You get that 2- (6,7,8,9-Tetrahydro-dibenzothiophen-2-yloxy) -octanoic acid nitrile as a slightly yellow colored oil, n ^: 1.5657.

Analogously one obtains

from 6.13 g (30.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophen- 3-ol and 6.13 g (30.0 mmol) 2-bromo-octanoic acid nitrile 2- (6.7, 8,9-tetrahydro-dibenzothiophen-2-yloxy) octane

20 ° acid nitrile, n _ß : 1.5657, *

109841/1978

from 2.20 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 1.90 g (10.0 mmol) 2-bromo-heptanoic acid nitrile 2- (6.7, 8,9-Tetrahydro-dibenzothiophen-2-ylthio-heptanoic acid nitrile, n ° ° _{: 1.6017;}

from 2.20 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-3-thiol and 2.04 g (10.0 mmol) of 2-bromo-octanoic acid nitrile 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio) octanoic acid nitrile, n ^ °°: 1.5972.

109841/1978

Example 24

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 of abs. Ethanol is at 0 ° to 5 ° saturated with dry hydrogen chloride gas, then stirred for 20 hours at room temperature and then at 30 ° im Evaporated in vacuo. The remaining, crude 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid imidoethyl ester hydrochloride is treated with a solution of 2.0 g (approx. 30 mmol) of potassium hydroxide in 40 ml of ethanol and 5 ml of water for 24 hours refluxed. Then the reaction mixture is first concentrated, mixed with water and the remainder Ethanol evaporated in vacuo. The aqueous alkaline solution obtained is shaken with ether and then with 2rn. Acidified hydrochloric acid. The excreted, raw acid is taken up in ether, the ethereal solution is washed with water, dried with magnesium sulfate and evaporated. Crystallization of the residue from hexane gives 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid from m.p. 99-100 °.

109841/1978

Example 25

In a round bottom flask with a reflux condenser and stirrer 4.0 g (9.3 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -2-hexyl-malonic acid diethyl ester in a mixture of 10 ml of 5N sulfuric acid and 50 ml of glacial acetic acid for 20 hours boiled under reflux. After cooling, the reaction mixture is evaporated in vacuo and the remaining oily residue distributed between ether and water. After the ether phase has been separated off, it is first washed with water, then .Extracted with 100 ml of 2% potassium hydroxide solution.

The alkaline solution is acidified with concentrated hydrochloric acid (pH = 1) and the oil which precipitates out in ether recorded. The ethereal solution thus obtained is washed neutral with water, dried with magnesium sulfate and im Evaporated in vacuo », the crude 2- (6,7,8,9-tetrahydrodibenzofuran-2-yloxy) octanoic acid as a yellow OeI. After recrystallizing twice from hexane, the pure one is obtained Acid in the form of white crystals with a melting point of 99-100 °.

1098417197 8

Analogously one obtains

from 1.80 g (5.0 mmol) of 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 a melting point of 128-129 ° (from methanol-water);

from 2.71 g (5.0 mmoles) of 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 of m.p. 55-56 ° (from hexane);

from 0.8 g (2.2 mmol) of 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 of m.p. 144 ° (from benzene-hexane);

from 1.0 g (2.33 mmol) of 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 a melting point of 78-79 ° (from hexane);

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

1Q9841 / 1978

from 1.34 g (3, OmMoI) 2- (6,7,8,9-tetrahydro-dibenzofuranÄ? ylthio) -2-hexyl-malonic acid diethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-2-ylthio) -octanoic acid of m.p. 92-93 '(from hexane);

from 2.26 g (6.0 mmol) of 2- (6.7, S ^ -Tetrahydro-dibenzofuran-S-ylthio ^ -methyl-malonic acid diethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) propionic acid of melting point 133-134 ° (from methanol-water);

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

from 3.02 g (6.0 mmol) of 2- (6.7, e.g-Tetrahydro-dibenzofuran-S-ylthio) -2-decyl-malonic acid diethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -dodecanoic acid of m.p. 73.5-74.5 ° (from hexane);

from 3.35 g (6.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -2-tetradecyl-malonic acid diethyl ester 2- (6,7,8,9-TetrahydrD-dibenzofurane3-ylthio) -hexadecanoic acid of m.p. 69-70 ° (from methanol).

109841/1978

The 2-bromo-2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -2-hexyl-malonic acid diethyl used as starting material ester can, starting from 2-hexyl malonic acid diethyl ester, such as • be represented as follows:

aj 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) of bromine, the 2-bromo-2-hexyl-malonic acid diethyl ester as a colorless oil . _{B.p. n} ^ 107.5-108 °; nj °° _: 1.4552.

The 2-bromo-2-methyl-malonic acid diethylester.der is analogous 2-Bromo-2-decyl-malonic acid diethyl ester and the 2-bromo-2-tetradecyl-malonic acid diethyl ester are produced.

b) In a round bottom flask with a reflux condenser, drip tray, KnliiJiiihydroxid drying tube, stirrer and gas inlet tube one adds 18.83 g (0.1 mol) 6,7,8,9-tetrahydro-dibem: ofuran 2-ol to a solution of 2.3 g (0.1 mol) sodium in 200 ml Section. Acthanol under nitrogen. To the thus obtained light brown solution of the sodium phenolate is added dropwise Stir 32.3 g (0.1 mol) of 2-bromo-2-hexyl-malonic acid diethyl ester and reflux for 12 hours. After cooling, the precipitated sodium bromide is filtered off and the filtrate evaporates in vacuo. The brown one obtained in this way oily residue is taken up in ether, the ethereal

109841/1978

Solution washed neutral with water, dried with magnesium sulfate and evaporated again, whereby one yellow OeI received. This oil is purified by column chromatography (Silica gel 0.05-0.2 mm, Merck, benzene solvent). Those containing the desired ester Fractions are combined and evaporated. After drying in a high vacuum, the pure diethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -2-hexyl-malonic acid is obtained

22 °
as a pale yellow oil; n ^: 1.5114.

Analogously one obtains

from 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 2.53 g (10.0 mmol) of 2-bromo-2-methyl-malonic acid diethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -2-

20 ° methyl malonic acid diethyl ester, n_: 1.5285;

from 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 4.35 g (10.0 mmol) of 2-bromo-2-tetradecyl-malonic acid diethyl ester the 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -2-tetradecyl-malonic acid diethyl ester, n_: 1.5033;

from 1.88 g (10.0 mmol) 6.7, e ^ -Tetrahydro-dibenzofuran-S-ol and 2.53 g (0.01 mol) of 2-bromo-2-methyl-malonic acid diethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -2-methyl malonic acid diathy ester, n °: 1.5310;

/ 1978

from 3.76 g (20.0 mmol) o ^ S ^

ol and 6.46 g (0.02 mol) of 2-bromo-2-hexyl-malonic acid diethyl ester the 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -2-

20 ° hexyl malonic acid diethyester, n ": 1.5181;

from 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 4.35 g (10.0 mmol) of 2-bromo-2-tetradecyl-malonic acid diethyl ester 2- (6,7,8,9-tetrahydro ~ dibenzofuran-3-yloxy) 2-tetradecyl-malonic acid diethyl ester, η: 1.5053;

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

20 ° ylthio) -2-hexyl-malonic acid diethyester, n _ß : 1.5359 ;

from 2.04 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 2.53 g (10.0 mmol) of 2-bromo-2-methyl-malonic acid diethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio)

20 ° 2-methyl-malonic acid diethyl ester, n ': 1.5592;

from 2.04 g (10.0 mmol) 6,7,8,9-tetrahydro-dlbenzofuran-3-thiol and 3.22 g (10.0 mmol) of 2-bromo-2-hexyl-malonic acid diethyl ester the 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthlo) -2-hexyl-malonic acid diathy ester, n ^: 1.5412, ·

tO98A1 / t978

from 2.04 g (10 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-thiol and 3.79 g (10 mmol) <2-bromo-2-decyl-malonate diethyl ester the 2- (6,7, pg-

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

2n °
np: 1.5240.

10Ö8A1 / 1978

Example 26

In a round bottom flask with a reflux condenser and stirrer 3.0 g (6.9 mmol) of 2- (6 ', 7.8,9-tetrahydro-dibenzofuran-2-yloxy) -2-hexyl-malonic acid diethyl ester heated under reflux for 20 hours in 30 ml of 1N sodium hydroxide solution. After cooling down "the reaction mixture is acidified with 1N hydrochloric acid and extracted with ether. The ethereal solution is washed neutral with water, dried over magnesium sulfate and evaporated.

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

109841/1978

Example 27

A solution of 1.34 g (3.0 mmole) of 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -2-hexyl-malonic acid diethyl ester 3 ml of 5N sulfuric acid are added to 15 ml of glacial acetic acid and the mixture is refluxed in a nitrogen atmosphere for 24 hours. 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 gives a brown colored Oil which is purified by column chromatography on silica gel, Merck [elution with benzene and benzene-glacial acetic acid (20: 1) 1. The fractions containing the desired product are pooled and recrystallized from hexane. The 2- (6,7, 8,9-tetrahydro-.dibenzothiophen-2-yloxy) -octanoic acid is obtained from M.p. 90-91 °.

Analogously one obtains

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

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

109841/1978

from 1.85 g (4.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio) 2-hexyl-malonic acid diethyl ester the 2- (6,7,8,9-tetra-

20 ° hydro-dibenzothiophene-3-ylth-io) -octanoic acid, n ~: 1.5848 after chromatographic purification on silica gel, eluting 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 made as follows:

a) To a solution of 0.258 g (11.2 mmol) of sodium in 15 ml Absolute ethanol is added 2.29 g (11.2 mmol) 6,7, -8,9-tetrahydro-di benzothiophen-2-ol. With stirring and introduction of nitrogen 3.62 g (11.2 mmol) of diethyl 2-bromo-2-hexyl-malonic acid in 15 ml are added dropwise to this solution abs.Aethanol and the reaction mixture is refluxed for 4 hours. After cooling, the ethanol is evaporated in vacuo and the residue partitioned between water and ether. The separated and with water The washed ether phase is dried over magnesium sulfate and evaporated. The raw product is cleaned by column chromatography on silica gel [elution with benzene-hexane (2: 1)]. The 2- (6,7,8,9-tetrahydrodibenzothiophen-2-yloxy) -2-hexyl-malonic acid dimethyl ester is obtained,

ΟΛΟ

η £ ^υ : 1.5383.

109841/1978

Analogously one obtains

from 2.04 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-, 3-ol and 3.23 g (10.0 mmol) of 2-bromo-2-hexyl-malonic acid diethyl ester the 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) -2-

20 °
hexyl malonic acid diethyl ester, n _n : 1.5361;

from 1.0 g (4.54 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 1.47 g (4.54 mmol) of 2-bromo-2-hexyl-malonic acid diethyl ester 2- (6,7,8,9-tetrahydro-dibenzothiophene-2-

Of) O

ylthio) -2-hexyl-malonic acid diethyl ester, η *: 1.5598, ·

from 2.20 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophenes 3-thiol and 3.23 g (10.0 mmol) of 2-bromo-2-hexyl-malonic acid diethyl ester the 2- (6,7,8,9-tetrahydro-dibenzothiophene-3-

20 °
ylthio) -2-hexyl-malonic acid diethyl ester, n _ß : 1.5601;

INSPECTED

109841/1978

Example 28

To 2.68 g (6.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -2-hexyl-malonic acid diethyl ester a solution of 0.92 g of potassium hydroxide in 3 ml of water is added to 20 ml of methanol. With stirring and introduction of nitrogen is then the mixture was refluxed for 24 hours. After the solvent has evaporated, the residue is distributed between ether and 1N hydrochloric acid. The ether phase is washed with water, dry it over sodium sulfate and evaporate it in a vacuum. The resulting raw mixture is separated by column chromatography on silica gel [elution with benzene and benzene: glacial acetic acid (50: 1)]. You get the 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -octanoic acid, Mp. 90-91 ° (from hexane) and also a little 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -2-hexyl-malonic acid (beginning of decomposition at 119 °).

OfSIGINAL INSPECTED

109841/1978

Example 29

In a round bottom flask with a reflux condenser and stirrer 3.0 g (7.8 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -2-hexyl-cyanoacetic acid-ethyl ester in a solution of 50 ml of glacial acetic acid and 10 ml of 5N sulfuric acid for 20 hours boiled under reflux. After cooling, the reaction mixture becomes evaporated in vacuo and the remaining residue distributed between ether and water. The ether phase is separated off, washed neutral with water, dried with magnesium sulfate and then concentrated in vacuo. The crude 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid thus obtained is by column chromatography (silica gel, 0.05-0.2 mm, Merck, solvent benzene-glacial acetic acid 85:15) cleaned. Those containing the desired acid Fractions are combined, evaporated in vacuo and the oily residue obtained in this way is crystallized twice from hexane, pure 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid obtained from m.p. 99-100 °.

Analogously one obtains

from 1.15 g (3.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -2-hexyl-cyanoacetic acid ethyl ester the 2- (6,7,8,9- Tetrahydro-dibenzofuran-3-yloxy) -octanoic acid of melting point 78-79 ° (from hexane);

109841/1978

from 1.20 g (3, OmMoI) 2- (6,7,8,9-tetrahydro-dibenzofuran-2-ylthio) -2-hexyl-cyanoacetic acid ethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-2-ylthio) -octanoic acid with a melting point of 92-93 ° (from hexane);

from 4.00 g (10, OmMoI) 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -2-hexyl-cyanoacetic acid ethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -octanoic acid with a melting point of 62-63 ° (from hexane).

The ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -2-hexyl-cyanoacetate used as starting material can be made as follows:

a) In a round bottom flask with reflux condenser, dropping funnel, Potassium hydroxide drying tube, stirrer and gas inlet tube are added 18.8 g (0.1 mol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol to a solution of 2.3 g (0.1 mol) of sodium in 80 ml of absolute ethanol under nitrogen. To the thus obtained 27.6 g (0.1 mol) of 2-bromo-2-hexyl-cyanoacetic acid ethyiester are added dropwise to a brown solution of the sodium phenolate, while stirring and heated one hour each to 40, 50 and 70 °. It is then evaporated to dryness in vacuo. The residue is distributed between water and ether, the ether phase is separated off and washed with water. To Drying the ethereal solution with magnesium sulfate, it is evaporated again in vacuo. The oily residue

109841/1978

is purified by column chromatography (silica gel 0.05-0.2 mm, Merck, benzene solvent). The one you want Benzene fractions containing esters are combined and evaporated. The pure ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -2-hexyl-cyanoacetate is obtained as a hygroscopic yellow oil.

Analogously one obtains

from 1.88 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 2.76 g (10.0 mmol) of 2-bromo-2-hexyl-cyanoacetic acid ethyl ester 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -2-hexyl-

20 °
ethyl cyanoacetate, n ": 1.5245;

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

20 ° ethyl 2-hexyl cyanoacetate, n _ß : 1.5505;

from 6.12 g (30.0 mmol) o ^ .e ^
thiol and 8.28 g (30.0 mmol) of 2-bromo-2-hexylcyanoacetic acid 2- (6,7,8,9-tetrahydra-dibenzofuran-3-ylthio)

20 ° 2-hexyl cyanoacetic acid ethy ester, n _D : 1.5553.

109841/1978

Example 30

2.11 g (5 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -2-hexyi-cyanoacetic acid are placed in a round bottom flask equipped with a reflux condenser and stirrer in a solution of 1.0 g of potassium hydroxide in 25 ml of ethanol and 2.5 ml Water boiled under reflux for 20 hours. After cooling, the reaction mixture is evaporated in vacuo, the residue suspended in about 30 ml of water, with conc. Hydrochloric acid acidified and the resulting solid substance extracted exhaustively with ether, whereby only a small part goes into solution. The ether extracts are combined, washed neutral with water, dried over magnesium sulfate and evaporated. The thus obtained solid residue (1.6 g) is determined 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 two times Recrystallization from hexane gives:

pure 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid from m.p. 99-100 °.

109841/1978

- Ill -

Example 31

Be in a round bottom flask equipped with a reflux condenser and stirrer 1.0 g (2.6 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -2-hexyl-cyanoacetate in 20 ml 1-n. Hydroxide heated under reflux for 22 hours. To the reaction mixture is cooled with conc. Acidified hydrochloric acid and extracted with ether. The essential ones Solutions are washed neutral with water, dried over magnesium sulfate and evaporated. The thus obtained solid residue contains very little 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid. It is extracted with hot hexane, only a small part of the residue going into solution ".. After evaporation of the hexane extract the residue obtained is made of hexane. recrystallized. This gives pure 2- (6.7, 8,9-Tetrahydro-dibenzofuran-2-yloxy) -octanoic acid vom M.p. 99-100 °.

109841/1978

Example 32

With stirring and introduction of nitrogen, 2.31 g (6.0 mmol) of 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 of 5-n. Sulfuric acid refluxed for 48 hours. The reaction mixture is then evaporated in the Vacuum and distribute the residue between water and ether. The washed with water and dried over sodium sulfate The ether phase is again evaporated and the crude product by chromatography on silica gel [elution with benzene-glacial acetic acid (19: 1)] purified. After recrystallization of the pure fractions from hexane, 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) -heptanoic acid is obtained of m.p. 84-84.5.

Analogously one obtains

from 1.80 g (4.51 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -2-hexyl-cyanoacetic acid ethyl ester 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -octanoic acid with a melting point of 90 ° -91 ° (from hexane).

The ethyl 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) -2-pentyl-cyanoacetate used as starting material is made as follows:

a) With stirring and introduction of nitrogen, 0.588 g (L2.25 mmol) of sodium hydride (50%, in mineral oil) are added to a Solution Y ^ pgejjjßl g (12 ^ 25 mmol) 6,7,8,9-Tetrahydro-dibenzo-

thiophen-3-ol in 40 ml of abs. Dimethylformamide. After subsiding the evolution of hydrogen is heated to 90 for a further 5 minutes and then back to room temperature a solution of 3.21 g (12.25 mmol) of 2-bromo-2-pentyl-cyahacetic acid ethyl ester was rapidly added dropwise to the cooled reaction medium. The reaction mixture is refluxed for 2 1/2 hours, evaporated after cooling in vacuo and the residue partitioned between water and ether. The washed with water and the ether phase dried over sodium sulfate is evaporated again. The remaining crude product is cleaned thoroughly Chromatography on silica gel [elution with benzene-hexane (2: 1)], using pure 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) -

20 ° 2-pentyl cyanoacetic acid ethyl ester, n _Q : 1.5504, obtained. Analogously one obtains

from 2.04 g (10.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-2-ol and 2.62 g (10.0 mmol) of ethyl 2-bromo-2-hexyl-cyanoacetate methyl 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -2-hexylcyanoacetate.

ORIGINAL INSPECTED

109841/1978

Example 33

3.4 g (9.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -2-hexyl-malonic acid are boiled in 34 ml of xylene Vl hour under reflux. After cooling, the reaction mixture is completely evaporated in vacuo. The oily residue obtained in this way is recrystallized twice from hexane. Pure 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid is obtained in the form of white needles with a melting point of 99-100.

Analogously one obtains

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

from 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-tetrahydrodibenzofuran-2-yloxy) -hexadecanoic acid of m.p. 55-56 (from hexane);

from 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 of melting point 78-79 (from hexane);

from 1.95 g (5.0 mmol) 2- (6,7,8,9-tetrahydro-dibenzofuran-2-ylthio) -2-hexyl-malonic acid the 2- (6.7.8 _t 9-tetrahydro- dib6nzofuran-2-ylthio) octanoic acid with a melting point of 92-93 ° (from hexane);

109841/1978

from 1.95 g (5.0-niMol) 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -2-hexyl-malonic acid the 2- {6,7,8,9-tetrahydro-dibenzofuran · 3-ylthio) octanoic acid of melting point 62-63 ° (from hexane);

from 2.23 g (5.0 mmol) 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -2 -decyl-malonic acid the 2- (6,7,8,9-tetrahydro- dibenzofuran-3-ylthio) dodecanoic acid with a melting point of 73.5 ° -74.5 ° (from hexane).

The 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -2-hexyl-malonic acid used as the starting material can be obtained as follows:

a) 4.0 g (9.3 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -2-hexyl-malonic acid diethyl ester are in a solution of 2.5 g of potassium hydroxide in 10 ml of methanol and 1 ml of water Boiled under reflux for 20 hours. The reaction mixture is then diluted with 100 ml of water, twice with a little ether washed, the aqueous phase acidified with ice-cold concentrated hydrochloric acid and the resulting oil with ether extracted. The ethereal solution thus obtained is washed neutral with water, dried over magnesium sulfate and in vacuo gently evaporated. After drying in a high vacuum, the crude 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -2-hexylmalonic acid is obtained, that of very little (approx. 2%) 2- (6,7,8,9-tetrahydrodibenzo € uran-2-yloxy) -octanoic acid is contaminated. The malonic acid is obtained as a viscous, yellow oil that is not crystalline

109841/1978

and is implemented without further purification.

Analogously, one obtains from the corresponding diethyl esters

2- (6 _s 7,8 ₎ 9-tetrahydro-dibenzofuran-2-yloxy) ~ 2-methylmalonic acid,

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

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

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

2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -2-hexylmalonic acid and

2- (6,7,8, g-Tetrahydro-dibenzofuran-S-ylthio) -2-decylmalonic acid,

which can be used further as raw products.

10,984.1 ^ 1

Example 34

Analogously to Example 33, one obtains

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

from 1.20 g (approx. 3 mmol) of crude 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio) -2-hexyl-malonic acid the 2- (6,7,8,9-tetrahydro-

20 °

dibenzothiophen-3-ylthio) octanoic acid, n _Q : 1.5718 after chromatographic purification on silica gel, elution with benzene and benzene-glacial acetic acid (49: 1).

The starting materials are analogous to Example 33 a), but only boil for two hours

0.924 g (2.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) -2-hexyl-malonic acid diethyl ester respectively.

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

obtain.

109841/1978

Example 35

0.78 g (ca 2 mmoles) of crude 2- (6,7,8,9-tetrahydrodibenzothiophen-2-yloxy) -2-hexyl-malonic acid are heated under nitrogen for half an hour at 150 °. The decarboxylated crude product is purified by chromatography Silica gel [elution with benzene and benzene-glacial acetic acid (19: 1) 1. After recrystallization of the pure fractions from hexane, 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -octanoic acid is obtained, M.p. 90-91 °.

From 0.78 g (approx. 2 mmol) of crude 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) -2-hexyl-malonic acid is obtained by heating to 240-250 for 5 minutes and working up as above 2- (6,7,8,9-Tetrahydro-dibenzothiophen-3-yloxy) -octanoic acid of m.p. 106-107 (from hexane).

The starting materials are analogous to Example 33 a), but only boiling for two hours

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

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

obtain.

109841/1978

211345S

Example 36

In a round bottom flask with a reflux condenser, potassium hydroxide drying tube, Stirrer and gas inlet tube are 100 ml of abs. Benzene, 12.0 g (99 mmol) thionyl chloride and 0.5 ml Dimethylformamide and then 9.4 g (28 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid registered. After all the acid has dissolved, boil in for another 2 hours Reflux. After cooling, the clear, yellow solution is evaporated in vacuo and the oily residue that remains evaporated several times with benzene. The crude 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) obtained in this way -octanoic acid chloride is taken in 150 ml of abs. Aether and drip the so obtained ethereal solution of 500 ml ether saturated with Aimaoniak, creating a thick paste. Ammonia is passed into the reaction mixture for a further 3 minutes and the mixture is stirred for a further 10 minutes and then washes the reaction mixture neutral with water. The ether phase is dried with magnesium sulfate and evaporated, whereby the crude 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanamide in solid form. From ethanol-water the pure amide crystallizes with a melting point of 130-131 °.

Analogously to the instructions given above, one obtains

from 1.38 g (3.5 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -dodecanoic acid the 2- (6,7,8,9-tetrahydro-dibenzofuran-2-

yloxy) dodecanamide of melting point 112-112.5 ° (from ethanol);

109841/1978

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

from 1.57 g (5.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -heptanoic acid 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -heptanamide of melting point 145-146 (from ethanol);

from 1.65 g (5.0 mmol) 2- (6,7,8,9-tetrahydro-dibenzofuran ^ S-yloxy) -octanoic acid 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -octanamide of melting point 140-141 (from ethanol);

from 1.93 g (5.0 mmol) 2- (o ^ e ^

yloxy) dodecanoic acid 2- (6,7,8,9-tetrahydro-dibenzofuran-3 yloxy) dodecanamide, m.p. 131.5-132.5 (from ethyl acetate);

from 1.73 g (5.0 mmol) of 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 ° (from ethanol);

from 2.77 g (8.0 mmol) 2- (6,7,8 ^ -Tetrahydro-dibenzofuran-S-ylthio) -octanoic acid 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) octanamide, Mp. 107.5-109 ° (from ethanol-water).

10iiU-1/1 97t

$ 211345

Example 37

A solution of 3 g (7.24 mmoles) of ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) dodecanoate
in 10 ml of ethanol is heated to 100 for 40 hours with 20 g of ammonia at a maximum pressure of 45 bar. After evaporation and recrystallization of the residue obtained in this way, the pure 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -dodecanamide with a melting point of 131.5-132.5 is obtained.

109841/1978

Example 38

1.19 g (10.0 mmol) of thionyl chloride are added dropwise with stirring 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 abs. Benzene and 0.1 ml dimethylformamide. The reaction mixture is refluxed for 11/2 hours and then evaporated in vacuo. Excess thionyl chloride is removed by repeated addition of abs. Benzene and evaporation im Vacuum. The oily residue, the crude 2- (6,7,8,9-tetrahydrodibenzothiophen-3-yloxy) -octanoic acid chloride, is in 100 ml abs. Aether is taken and the ethereal solution with ammonia gas saturated. The mixture is stirred for a further 20 minutes and the reaction mixture is then washed with water. After drying the ether phase The crystalline crude product is recrystallized from acetone-hexane over magnesium sulfate and evaporation in vacuo. 2- (6,7,8,9-Tetrahydro-dibenzothiophen-3-yloxy) -octanamide is obtained from m.p. 142-143.

Analogously one obtains

from 1.73 g (5.0 mmol) of 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 ° (from methanol);

109841/1978

from 1.74 g (5.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) -heptanoic acid 2- (6,7,8,9-tetrahydro-dibenzothiophen · 2-ylthio) -heptanamide of melting point 150-150.5 ° (from methanol) j

from 1.81 g (5.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio) -octanoic acid 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio) -octanamide of m.p. 106-109 (from methanol).

109841/197 "

Example 39

In a round flask with stirrer, potassium hydroxide drying tube, A solution of 1.1 g (4.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -heptanoic acid nitrile is added to the gas inlet tube and thermometer in 40 ml abs. Chloroform and 2 ml of abs. Methanol with stirring at 5-8 ° for 10 minutes saturated dry hydrogen chloride and then stirred for 4 hours at room temperature. Then the reaction solution evaporated in vacuo and the remaining, oily residue about 3 minutes in vacuo to remove the methyl chloride formed heated to 90. The solid residue obtained in this way is made from ethanol with the addition of activated charcoal recrystallized twice. Pure 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -heptanamide is obtained in this way in the form of white needles with a melting point of 145-146.

Analogously one obtains

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

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

1 09841/1978

from 1.84 g (5.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -dodecanoic acid nitrile 2- (6,7,8,9-Tetrahydradibenzofuran-2-yloxy) -dodecanamide with a melting point of 112-112.5 ° (from Ethanol);

from 3.11 g (10.0 mmol) of 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 (from ethanol);

from 1.84 g (5.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -dodecanoic acid nitrile 2- (6,7,8,9-tetrahydrodibenzofuran-3-yloxy) -dodecanamide of melting point 131.5-132.5 ° (from ethyl acetate);

from 1.64 g (5.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-ylthio) -octanoic acid nitrile the 2- (6,7,8,9-tetrahydro-dibenzo- Uran-2-ylthio) octanamide of melting point 135-136 (from ethanol);

from 1.64 g (5.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -octanoic acid nitrile 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -octanamide of melting point 107.5-109 ° (from ethanol-water).

109841/1978

211345S

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 abs. Chloroform and 4 ml of abs. Methanol is passed through dry hydrogen chloride gas until saturation, whereby care should be taken that the temperature does not rise above 5. The reaction mixture is left with stirring for a further 4 hours Stand at room temperature and finally evaporate it in vacuo. The oily residue is 10 minutes in a water jet vacuum heated to 90. Methyl chloride is split off with foaming. The desired product falls directly into crystalline form. After recrystallization from methanol the 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -octanamide is obtained of m.p. 116-117 (from methanol).

Analogously one obtains

from 1.50 g (4.58 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) -octane-curenitrile 2- (6,7,8,9-tetrahydro ~ dibenzothiophen-3-yloxy) octanamide of m.p. 142-143 (from acetone-hexane);

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

109841/1978

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

109841/1978

211345S

Example 41

Place 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 of abs. Ethanol at 0-5 ° with dry hydrogen chloride saturated, then stirred for 20 hours at room temperature and then evaporated at 30 in a vacuum. The residue is taken up in 40 ml of dioxane, 4 ml of water is added and the resulting solution is stirred at 40 for 3 hours. Then it will be evaporated again, the residue taken up in benzene, the benzene solution dried over magnesium sulfate and again evaporated. After drying for one hour at 100 and 0.1 torr, the crude ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) octanoate is obtained, which is purified by column chromatography (silica gel 0.05-0.2 mm, Merck, benzene solvent) will. The benzene fractions containing the desired ester are combined and evaporated. After drying The pure ethyl 2- (6,7,8,9-tetrahydrodibenzofuran-2-yloxy) octanoate is obtained in a high vacuum as pale yellow

ooO

OeI, n ^: 1.5227.

Analogously one obtains

from 2.41 g (10.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -propionitrile the 2- (6,7,8,9-tetrahydro-dibenzofuran

109841/1978

20 °

2 ~ yloxy) propionic acid ethyl ester, n ~: 1.5408;

from 2.97 g (10.0 mmol) 2- (6,7,8,9-tetrahydro-dibenzofuran-2-

yloxy) -heptanoic acid nitrile 2- (6,7,8,9-tetrahydro-dibenzofuran

20 °

2-yloxy) -heptanoic acid ethyl ester, n ^: 1.5241;

from 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

22 ° 2-yloxy) dodecanoic acid ethyl ester, n _Q : 1.5133;

from 4.23 g (10.0 mmol) 2- (6,7,8,9-tetrahydro-dibenzofuran-2-

yloxy) hexadecanoic acid nitrile den 2 ~ (6,7,8,9-tetrahydro-dibenzo-

20 ° furan-2-yloxy) -hexadecanoic acid ethyl ester, n _Q : 1.5062;

from 3.11 g (10.0 mmol) 2- (6,7,8,9-tetrahydro-dibenzofuran

3-yloxy) octanoic acid nitrile denotes 2- (6,7,8,9-tetrahydro-dibenzofuran

20 ° 3-yloxy) octanoic acid ethyl ester, n ~: 1.5233;

from 3.27 g (10.0 mmol) 2- (6,7,8,9-Tetrahydro-dibenzoEuran-2-

ylthio) octanoic acid nitrile 2- (6,7,8,9-tetrahydrο-dibenzofuran

90 °

2-ylthio) octanoic acid ethyl ester, n ^: 1.5465;

from 3.27 g (10.0 mmol) 2- (ö ^ .S ^ -
ylthio) octanoic acid nitrile denotes 2- (6,7,8,9-tetrahydro-dibenzofuran

20 °

Ethyl 3-ylthio) octanoate, n ^: 1.5517.

103841/1978

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

2O °
methyl ester, n ^: 1.5320.

1098417

Example 42

3.11 g (10.0 mmol) of 2- (6,7,8,9-tetrahydrodibenzofuran-2-yloxy) octanoic acid nitrile are added to a mixture of 50 ml of ethanol, 5 ml of water and 3 ml of 307 ₀ aqueous hydrogen peroxide solution at 20 with 1.0 ml 2-n. Sodium hydroxide solution added. After the evolution of oxygen has subsided, the reaction solution is warmed to 50 for a further 30 minutes and then strongly concentrated in vacuo. The concentrate is distributed between chloroform and water, the chloroform phase is washed with water, dried over potassium carbonate and the solvent is evaporated off. The residue is crystallized from ethanol-water, the 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) octanamide having a melting point of 130-131 °.

109841/1978

2113A55

Example 43

A solution of 1.50 g (4.58 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -octanoic acid nitrile in 50 ml abs. Chloroform and 5 ml of abs. Ethanol is saturated with dry hydrogen chloride at 0-5, 15 hours at room temperature stirred and then evaporated at 30 in a vacuum. The residue is taken up in 20 ml of dioxane and 4 ml Water on and the reaction mixture is stirred for a further 5 hours at 40. After evaporation in vacuo, the reaction product is in Benzene added, the benzene solution dried over magnesium sulfate and evaporated again. The cleaning of the The crude product is carried out by chromatography on silica gel [elution with benzene-hexane (2: 1)], wherein the 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -octanoic acid ethyl ester,

? 0 °
rip: 1,5498, received.

Analogously one obtains

from 2.62 g (8.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) -octanoic acid nitrile the 2- (6,7,8,9-tetrahydro-dibenzo-

20 °

ethyl thiophen-3-yloxy) octanoate, η ~: 1.5481;

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

20 ° dibenzothiophen-2-ylthio) heptanoic acid ethyl ester, n _n : 1.5787;

10 9841/197 8

from 1.72 g (5.0 mmol) 2- (6,7,8,9-tetrahydro-dibenzothiophene-

3-ylthio) octanoic acid urenitrile 2- (6,7,8,9-tetrahydro-

20 °

ethyl dibenzothiophen-3-ylthio) octanoate, η: 1.5754.

109341/1978

Example 44

To a solution of 1.1 g (11.0 mmol) of difsopropylamine in 8 ml abs. Tetrahydrofuran is added to butyllithium in hexane (5.2 ml of a 2.12 molar Solution, corresponding to 11.0 mmol) and keep the temperature below 0. It is added to the cold basic solution thus obtained 1.23 g (5.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -acetic acid in small portions and continue to stir below 0. After a further 15 minutes, the color now turns yellow Solution at 5 2.03 ml (11.5 mmol) of hexamethylphosphoric triamide was added dropwise and then another 15 minutes stirred, the color of the solution turning brown. It is then cooled to 0 and 0.745 ml (5.3 mmol) n-Hexyl bromide, the temperature rising to 10. The mixture is stirred for a further 2 hours at room temperature, then acidified at 0 ° with 2-ru hydrochloric acid, add 50 ml of water and Mthert from. The ethereal solution obtained in this way is mixed with approx. 40 ml of 0.5-n. Sodium hydroxide extracted, the alkaline extract acidified again with hydrochloric acid and extracted again with ether. .

After drying over magnesium sulfate, the essential solution evaporated in vacuo. This gives a brown oil which, in addition to the desired 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid among others Impurities nor those used as the starting material. 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -acetic acid

109841/1978

holds. The oil is purified by column chromatography [Neutral silica gel 0.05-0.2 mm Merck, solvent benzene-glacial acetic acid (9: 1)]. Those containing the desired acid Fractions are combined and evaporated, and the solid residue thus obtained is recrystallized twice from hexane. Man receives pure 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -octanoic acid from Srnp. 99-100.

Analogously one obtains

from 1.23 g (5.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -acetic acid and 0.745 ml (5.3 mmol) of hexyl bromide 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -octanoic acid from M.p. 78-79 ° (from hexane).

The 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -acetic acid used as starting material is obtained as follows:

a) To a solution of 1.15 g (50, OmMoI) sodium in 20 ml abs. Ethanol is added 9.40 g under nitrogen (50.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol. 9.2 g (55.0 mmol) of ethyl 2-bromoacetate are then added dropwise with stirring and reflux for 4 hours. After cooling, the reaction mixture is evaporated in vacuo and distributes the residue between water and ether. The ether phase is washed with water over magnesium sulfate

109841/1978

dried, evaporated and the remaining crude product by column chromatography on neutral silica gel (0.05 0.2 mm Merck, solvent benzene) purified from few starting materials. The obtained ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -acetate is crystallized from ethanol, melting point 75-76 °.

Analogously one obtains

from 3.76 g (20.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol and 3.67 g (22.0 mmol) of ethyl 2-bromoacetate, ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -acetate of m.p. 54-55 (from hexane).

b) 8.22 g (30.0 mmol) of ethyl 2- (6,7,8,9-tetrahydrodibenzofuran-2-yloxy) -acetate are refluxed for 4 hours in a solution of 3.36 g (60.0 mmol) of potassium hydroxide in 100 ml of methanol and 10 ml of water. After this Cooling, the reaction mixture is evaporated, the residue is partitioned between dilute hydrochloric acid and ether and separated the ether phase and extracted the hydrochloric acid phase with ether. The combined ethereal solutions are mixed with water washed neutral, dried over magnesium sulfate and evaporated. The remaining crude 2- (6,7,8,9-tetrahydrodibenzofuran-2-yloxy) acetic acid is recrystallized from ethanol, melting point 185-186 °.

109841/1978

Analogously one obtains

from 4.0 g (14.6 mmol) of ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -acetate 2- (6,7,8,9-tetrahydrodibenzofuran-3-yloxy) acetic acid of melting point 163-165 (from ethanol-water).

109841/1978

Example 45 .

Analogously to example 44 one obtains

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

Similarly to Example 44, one obtains

from 1.31 g (5.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -acetic acid and 0.745 ml (5.3 mmol) of hexyl bromide 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -octanoic acid from M.p. 62-63 (from hexane);

from 1.31 g (5.0 mmol) of 2- (o ^ jS ^ -Tetrahydro-dibenzofuran-S-ylthio) -acetic acid and 1.042 g (5.3 mmol) of decylbroraid die. 2- (6,7,8,9-Tetrahydro-dibenzofuran ~ 3-ylthio) -dodecanoic acid from M.p. 73.5-74.5 ° (from hexane).

The 2- (6,7,8,9-tetrahydro · dibenzofuran-2-ylthio) acetic acid is obtained as follows:

a) To a solution of 0.46 g (20.0 mmol) of sodium in 40 ml of abs. Ethanol is added 4.08 g (20.0 mmol) of 6,7,8,9-tetrahydro-dibenzofuran-2-thiol. A solution prepared in the same way is added to the sodium salt solution thus obtained of the sodium salt of 2.78 g (20.0 mmol) of 2-bromoacetic acid in

109841/1978

- 1J7 -

80 ml abs. Ethanol and the mixture refluxed for 4 hours. After cooling, the reaction mixture is suction filtered and the filtrate evaporated in vacuo. The residue is dissolved together with the Nutschengut in water, the aqueous solution decolorized with activated charcoal and treated with conc. Acidified hydrochloric acid. The precipitated crude product is filtered off with suction and recrystallized from ethanol-water. The received 2- (6,7,8,9-Tetrahydro-dibenzofuran-2-ylthio) -acetic acid melts at 122-123 °.

Analogously one obtains

from 4.08 g (20.0 mmol) 6.7, e ^ -Tetrabydro-dibenzofuran-S-thiol and 2.78 g (20.0 mmol) of 2-bromoacetic acid, 2- (6,7,8,9-tetrahydro-dibenzofuran-3-ylthio) -acetic acid of m.p. 103.5-104.5 (from ethanol-water).

109841/1978

Example 46

To a solution, cooled to -10 °, of 1.11 g (11.0 mol) of diisopropylamine in 10 ml of abs. Tetrahydrofuran 5.2 ml of a 2.12 molar solution of butyllithium in hexane (11.0 mmol) are added dropwise while stirring and passing in nitrogen. The reaction mixture is then added in portions with 1.39 g (5.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) -acetic acid added, taking care that the temperature does not rise above -5 °. The mixture is stirred for 30 minutes at 0, then 2.06 g (11.5 mmol) of hexamethylphosphoric triamide are added dropwise and the mixture is stirred for a further 30 minutes at -5 to 0 °. Finally, at -5 °, 0.875 g (5.3 mmol) of freshly distilled hexyl bromide are added and the mixture is stirred for a further 2 hours Room temperature. The reaction mixture is then partitioned between dilute hydrochloric acid and ether. After drying the Ether extracts over sodium sulfate and evaporation in vacuo the crude product is purified by chromatography on silica gel [elution with benzene and benzene-glacial acetic acid (50: 1)]. 2- (6,7,8,9-Tetrahydro-dibenzothiophen-2-ylthio) -octanoic acid is obtained of m.p. 91-92 (from hexane).

Analogously one obtains

from 1.39 g (5.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio) -acetic acid and 0.875 g (5.3 mmol) of hexyl bromide

109841/1978

2- (6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio) -octanoic acid,

n _ß : 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). So you get

a) from 1.76 g (8.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol and 1.112 g (8.0 mmol) of bromoacetic acid or 2- (6,7,8,9 tetrahydro-dibenzothiophen-2-ylthio) -acetic acid of m.p. 132-134 ° (from ether-hexane);

from 1.76 g (8.0 mmol) o ^ jS ^ -Tetrahydro-dibenzothiophene-S-thioi and 1.112 g (8.0 mmol) of bromoacetic acid, 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-ylthio) -acetic acid.

109841/1978

Example 47

Analogously to example 46 one obtains

from 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 the 2- (6, 7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -octanoic acid with a melting point of 90 ° -91 ° (from hexane);

from 2.62 g (10.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothIophen-3-yloxy) -acetic acid and 1.70 g (10.3 mmol) of hexyl bromide 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) -octansMure vom M.p. 106-107 (from hexane).

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

. a) From 5.10 g (25.0 mmol) of 6,7,8,9-tetrahydro-dibenzotMophen-2-ol and 4.18 g (25.0 mmol) of ethyl bromoacetate, the 2- (6, 7,8,9-Tetrahydro-dibenzothiophen ~ 2-yloxy) -acetic acid ethyl ester of melting point 112-113 (from ethanol) , and

from 5.10 g (25.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophane-3-oil and 4.18 g (25.0 mmol) ethyl bromoacetate the 2 ~ (6,7,8, 9 · Tetrahydro-dibenzothiophen-3-yloxy) -ess ⁴ ^ acid stylists.

b) From 4.35 g (15.0 mmol) of 2- (6,7,8,9-tetrahydro-dibenzothiophene-2-yloxy) acetic acid ethyl ester yields the 2- (6,7 ₉ S, 9-

109841/1978

Tetrahydro-dibenzothiophen-2-yloxy) acetic acid with a melting point of 218-220 ° (from ethanol), and

from 4.35 g (15.0 mmol) of 2- (6,7,8,9-tetrahydro-dibeneothiophen-3-yloxy) -acetic acid ethyl ester 2- (6,7,8,9-tetrahydrodibenzothiophen-3-yloxy) acetic acid.

109841/1978

Example 48

7.52 g (4.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-2-ol and 14.2 g (8.0 mmol) of 1,1,1-trichloro-2-methyl-2-propanol (Acetoncäiloroform) are dissolved in 130 ml of distilled acetone, the solution cooled to 0 ° and pulverized with 4.27 g Sodium hydroxide (one third of a total of 12.8 g = 320 mmol) was added. The temperature is left within while stirring 2 hours increase to 25. After cooling again to 0, the second portion of 4.27 g of sodium hydroxide is added and added the same working method, the last portion after 2 hours. Again, the temperature is left within 2 hours 25 increase. The mixture is stirred for a further 5 hours at this temperature and then evaporated in a rotary evaporator. The residue is dissolved in water, the dark solution with conc. Acidified hydrochloric acid and extracted with ether. the Aether solution is in turn with 2-n. Sodium bicarbonate solution extracted and the alkaline extract 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 acid thus purified is in 100 ml Dissolved methanol, decolorized the solution with activated charcoal and then added 90 ml of water. The precipitated crystals are filtered off and recrystallized again from methanol-water. M.p. of the pure acid 136.5-138 °.

Analoj »is obtained using the« oil bon NongtMi 109841/1978

SAD ORIGiNAL

ljljl-trichloro ^ -methyl ^ -propanol, sodium hydroxide and acetone

from 7.52 g (4.0 mmol) 6,7,8,9-tetrahydro-dibenzofuran-3-ol 2- (6,7,8,9-tetrahydro-dibenzofuran-3-yloxy) -2-methylpropionic acid of m.p. 78-80 ° (from hexane);

from 8.16 g (4.0 mol) 6,7,8,9-tetrahydro-dibenzofuran-2-thiol 2 ~ (6,7,8,9-tetrahydro-dibenzofuran-2-ylthio) -2-methylpropionic acid of m.p. 146-147 (from ether-hexane);

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

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

from 8.16 g (4.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophen-3-ol the 2- (6,7,8,9-tetrahydro-dibenzothiophen-3-yloxy) -2-methylpropionic acid ;

from 8.80 g (4.0 mmol) 6,7,8,9-tetrahydro-dibenzothiophene-2-thiol 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-ylthio) -2-methyl-prop ionic acid;

from 8.80 g (4.0 mmol) 6.7, e 1-tetrahydro-dibenzothiophene-S-thiol 2- (6,7,8,9-tetrahydro-dibexizothiophene-3-yLthLo) 2-methyl-propionic acid.

109841/1978

Example 49

1.1 g (3.5 mmol) of 2- (6,7,8,9-tetrahydro-dibenzofurans 2-yloxy) -heptanoic acid in 20 ml of abs. Dissolved ethanol. A solution of 69 mg (3.0 mmol) of sodium in 5 ml of abs is added to the resulting solution. Ethanol, evaporates to dryness and rub the white, solid residue with approx. 20 ml of ether. Then it is sucked off and washed with ether. The pure sodium salt is obtained as a white powder which melts between 290-308 ° with decomposition.

109841/1978

Example 50

Analogously to example 49 one obtains

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

1Q9G4 1 / ": 'i'-li

Example 51

110 mg (2.75 mmol) of calcium are decomposed in 10 ml of water under nitrogen. 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 was added and the mixture was refluxed for 15 minutes. After cooling, the resulting white suspension becomes concentrated to approx. 20 ml, the crude calcium salt which precipitates is filtered off with suction and washed with a little ether. Afterward it is extracted three times with 120 ml of boiling methanol each time. The methanol extracts are combined, filtered and reduced to approx. Concentrated to 20 ml, the calcium salt crystallizing out. The methanol phase is diluted with approx. 30 ml of ether, Then sucks off the crystals and washes them 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 between 305-315 ° with decomposition.

109841/1978

Example 52

To a suspension of calcium hydroxide made by decomposing 137 mg (3.42 mmol) of calcium in 15 ml of water a solution of 2.50 g (7.2 mmol) of 2- (6,7,8,9-tetrahydrodibenzothiophen-2-yloxy) octanoic acid is added with stirring and introduction of nitrogen in 80 ml of 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 twice from abs. Recrystallized methanol. The pure calcium salt is obtained in this way of 2- (6,7,8,9-tetrahydro-dibenzothiophen-2-yloxy) -octanoic acid, which turns brown between 290 and 305 decomposed.

109841/1978

Claims (1)

Claims 1.) Process for the production of aryloxy or arylthioalkanoic acids, their salts and functional derivatives of the general formula I in which R _{1 is} an alkyl group with a maximum of 14 carbon atoms or a cycloalkyl group with 5-7 carbon atoms, R.2 hydrogen or the methyl group,
Ro is the hydroxyl group in which the hydrogen atom can be replaced by an alkali metal or an alkaline earth metal, an alkoxy group with at most 3 carbon atoms
or the amino group, and X and Y independently of one another are oxygen or
Sulfur mean characterized in that an alkali metal salt of a phenol or a thiophenol of the general formula II 109841/1978 in which X and Y have the meaning given under the formula I, with a compound of the general formula III A-C-CO-Ro (HI) I. R ₂ in which R ₁ , Ry and R _{0 have} the meaning given under the general formula I and A signifies halogen, an alkylsulfonyloxy or an arylsulfonyloxy group. 21134SS 2. Process for the preparation of aryloxy or arylthioalkanoic acids of the general formula Ia X-C-COOH - \ H Ro in which R ₁ , R ₂ , X and Y are those in claim 1 have given meaning, and their salts with alkali and alkaline earth metals, characterized in that one is a functional derivative hydrolyzed by such an acid. "^ ÖAD OfttGlNAL 109841/1978 -.153 - 3. Process for the preparation of aryloxy- or arylthioalkanoic acids of the general formula Ib X-CH- CDOH, _Ib) -JH in which R ₁ , X and Y are those in claim 1 have given meaning, and their salts with alkali or alkaline earth metals, characterized in that compounds of the general formula IV Y- \ ^x y ^z i -JHZ ₀ in which R ,, X and Y in claim 1 ■ have given meaning and _{Z 1 and Z 2,} independently of one another, denote lower alkoxycarbonyl or nitrile groups, heated under hydrolyzing conditions until one of the groups Z or Z 2 is completely hydrolyzed and hydrogen is present instead of the others. 109841/1978 4. Process for the production of aryloxy or ^ arylthioalkanoic acids, their salts with alkali and alkaline earth metals, their lower alkyl esters and amides of the general formula Ic (Ic) in which R ,, Ro, X and Y those in the claim have given meaning, characterized in that one compound of the general Formula V fl -! X - C - CORo ΛΛ S. ■ IJ v ^v ' -J H COOH in which R ,, R-, X and Y those in the claim have given meaning, until the splitting off of the equimolar ren amount of carbon dioxide heated. 109841/1978 5. Process for the preparation of aryloxy or arylthioalkanoic acid amides the general formula Id λ Χ - C - COMH, -3 H. i
R. (Id) in which Κ. ,, R ₂ , X and Y have the meaning given in the claim, characterized in that an aryloxy or arylthioalkanoic acid derivative of the general formula VI R, 0 ι ¹ II -C-C-B (VI) in which R ,, R ₂ , X and Y are those in claim have given meaning, and B halogen or an alkoxy group means, reacts with ammonia. 109841/1978 ..- 156 - 6. Process for the preparation of aryloxy or arylthioalkane acid amides of the general formula Id in which Rp R ₂ , X and Y have the meaning given in claim ", characterized in that a nitrile of the general formula VII -CC = M _(VII) R ₂ in which Rp R ₂ , X and Y have the meaning given in the claim, water is added. 109841/1978 -, 157 .- • 7 «Process for the production of aryloxy or arylthioalkanoic acid esters of the general formula Ie R. OgOi * "L in which R ,, R ₂ , X and Y in claim 1 ■ -. have the meaning given and Rg ¹ denotes a lower alkyl radical having 1-3 carbon atoms, characterized in that a nitrile of the general Formula 'VII _Ώ ^K l ι ^ ri x - c - cs N _(VII) ¹ - 'i H Ro in which R ^, R2, X and Y are those in the claim Have given meaning, in the presence of water and mineral acid with a lower alkanol. 109841/1978 8. Process for the preparation of aryloxy or alkanoic acids of the general formula Ia given in claim 2, in which R ,, Ro ' ^{X uni} * ^ ^ ^e * ^m claim 1 have the meaning given, and their salts with alkali and alkaline earth metals , characterized in that a bis-alkali metal or bis-halogen magnesium compound of a carboxylic acid of the general formula VIII, X-C-CO-OH (VIII) 'HR ₂ in which X, Y and R _{0 have} the meaning given under the formula I, with the essentially equimolar amount of a compound of the general formula IX, R ₁ -A (IX) in which R has the meaning given in claim 1 and A is halogen, an alkylsulfonyloxy or an arylsulfonyloxy group means, reacts, optionally from the obtained salt of a carboxylic acid of the general Formula Ia releases the latter and if desired again converted into an alkali or alkaline earth metal salt. 109841/1978 9. Process for the preparation of aryloxy or arylthioalkanoic acids the general formula If, (If) in which X, Y and R ^ are specified in claim 1 Have meaning, and their salts with alkali and alkaline earth metals, characterized in that one is a compound the general formula II given in claim 1, in which X and Y have the meaning given there, with a methane tri- or tetrasubstituted by chlorine and / or bromine and a ketone of the general formula X, R ₁ -CO- CH ₃ (X) in which R has the meaning given in claim 1, or with the reaction product of the latter two components, a compound of the general formula XI, CH ₃
HO-C- CHaI ₃ (XI) in which Hal is chlorine or bromine and R- has the meaning given in claim 1, in Reacts the presence of at least four times the molar amount of a strong base, optionally from the one obtained Salt of a carboxylic acid of the general formula If die 109841/1978 the latter releases and, if desired, again in an alkali or Alkaline earth metal salt transferred. 10. Compounds of the general formula I in whichever R ,, Rp, R.j, X and Y specified in claim 1 Have meaning. 11. 2- (6,7,8,9-tetrabydro-dibenzofuran-2-yloxy) -octanoic acid and their alkali and alkaline earth metal salts. i 12. 2- (6,7,8,9-Tetrahydro-dibenzofuran-2-yloxy) -dodecanoic acid and their alkali and alkaline earth metal salts. 109841/1978 13. 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-yloxy) -octanoic acid " and their alkali and alkaline earth metal salts. 14. 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-yloxy) -dodecanoic acid and their alkali and alkaline earth metal salts. 15. 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-ylthio) -octanoic acid and their alkali and alkaline earth metal salts. 16. 2- (6,7,8,9-Tetrahydro-dibenzofuran-3-ylthio) -dodecanoic acid and their alkali and alkaline earth metal salts. 17. 2- (6 _> 7,8,9-Tetrahydro-dibenzofuran-2-ylthio) -octanoic acid and its alkali and alkaline earth metal salts. 18. 2- (6,7,8,9-Tetrahydro-dibenzothiophen-3-yloxy) -octanoic acid and their alkali and alkaline earth metal salts. 19. 2- (6,7,8,9-Tetrahydro-dibenzothiophen-3-ylthio) -octanoic acid and their alkali and alkaline earth metal salts. 20. 2- (6,7,8, g-Tetrahydro-dibenzothiophene-1-ylthio) -octaneäiira and their alkali and alkaline earth meta! j-lsa} .ze. 21. 2- (6.7.8 _J 9 »tetrahydro-dibenzofuran-2-yloxy) -qctanamide. 22. Ethyl 2- (6,7,8,9-tetrahydro-dibenzofuran-2-yloxy) -heptanoate. 109841/1978 23. Compounds of the general formula Ha, (Ha) in which X and Y have the meaning given in claim 1 to have. 24. Compounds of the general formula Hb, (Hb) in which X has the meaning given in claim 1. 25. 6,7,8,9T-tetrahydro-dibenzofuran-2-thiol 26. Compounds of the general formula VJIIa, X-Ci ₂ -COi-OH (Villa) in which X and Y have the meaning given in claim 1 to have. 109841/1978 21T345S 27. Pharmaceutical preparations, characterized by a content of at least one compound of the claim given general formula I, in combination with an inert carrier and optionally others Aggregates. Administration therapeutically we] _M mn "ι Μι ι ι 11 of at least one Vi iiiiinTunM dfT fin Αιιί [ιμιι1ι 1 specified general FO 3.34 / WOE / vB 109841/1978