CA1104144A - Dibenzothiophenes derivatives - Google Patents

Abstract

Abstract The invention relates to compounds of the formula 1 wherein R is hydrogen, halogen, hydroxy, cyano, lower alkyl, hydroxy-lower alkyl, lower alkoxy, acyl, benzyloxy, lower alkyl-thio, trifluoromethyl, nitro, amino, mono-lower alkylamino, di-lower alkylamino, sulfamoyl, di-lower alkylsulfamoyl or difluoromethylsulfonyl; R1 is halogen, cyano, lower alkyl, hydroxy-lower alkyl, lower alkoxy, acyl, acylamido, benzyloxy, lower alkylthio, trifluoromethyl, hydroxy, nitro, amino, mono-lower alkylamino, di-lower alkyl-amino, sulfamoyl, di-lower alkylsulfamoyl or difluoromethylsulfonyl, or R taken together with an adjacent R1 is also lower alkylenedioxy; R2 is wherein A is hydroxy, lower alkoxy, amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or di-loweralkylamino-lower alkoxy, X and Y, independently, are hydrogen or lower alkyl, and m is 1 to 7, or R2 is wherein B is hydroxy, carboxy, lower alkoxy, amino, hydroxyamino, mono-lower alkylamino, di-lower alkylamino, amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy, Y and X, independently, are hydrogen or lower alkyl; and n is 1 to 7;
when X and Y are different, their enantiomers; when B is hydroxy or carboxy, salts thereof with pharmaceutically acceptable bases; and when R or R1 is amino, mono-lower alkyl-amino or di-lower alkylamino, and/or when B or A is amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy, addition salts thereof with pharmaceutically acceptable acids prepared inter alia, from the correspondingly substituted thiophenol and haloketo-cyclohexane are described. The dibenzothiophenes of the invention are useful antiinflammatory, analgesic and antirheumatic agents.

Description

The invention relates to a process for the preparation of compounds of the formula f~.~, R2 wherein R is hydrogen, halogen, lower alkyl or di-lower alkylamino; Rl is halogen, lower alkyl or di-lower alkylamino;

R2 iS -(C~A, wherein ~ is hydroxy or A is n -C-B wherein B is hydroxy, lower alkoxy, amino or di-lower alkylamino-lower alkoxy, Y and X, independently, are hydrogen or lower alkyl;
and n is 1 to 7;
when X and Y are different, of their enantiomers; of salts thereof with pharmaceutically acceptable bases; and of addition salts thereof with pharmaceutically acceptable acids.
As used herein, the term "lower alkyl" denotes a straight or branched chain hydrocarbon group containing 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, neopentyl, pentyl, heptyl and the like. The term "halogen" denotes the halogens, that ~ f~f~

is bromine~ chlorine, fluorine and iodine; bromine and chlorine are preferred.
Exemplary of di-lower alkylamino are dimethyl-amino, diethylamino and the like. Exemplary of di-lower alkylamino-lower alkoxy are dimethylaminomethoxy, diethylaminoethoxy and the like.
Preferred dibenzothiophenes of the invention are those characterized by the formulas ~ C - COOH
Y

and R ~ C~ C~20~

wherein R'l is halogen or lower alkyl, prefexably R'l is halogen, and X and Y are as previously described, their enantiomers when X and Y are different, and salts of the compounds of formula I' with pharmaceutically acceptable bases.

Preferred compounds of ~ormula I are:
racemic 8-chloro-a-methyl-dibenzothiophene-3-acetic acid;
(~) 8-chloro-~-methyl-dibenzo~hiophene-3-acetic acid;
(-) 8-chloro-a-methyl-dibenzothiophene-3-acetic acid;

2-(8-chloro-3-dibenzothienyl)ethanol;
8-chloro-dibenzothiophene-3-acetic acid;
8-chloro-dibenzothiophene-3-acetamide.
Exemplary of compounds of this invention corresponding to formula I are:
racemic 2-(8-chloro-3-dibenzothienyl)propanol;
8-chloro-dibenzothiophene-3-acetic acid;
8-chloro dibenzothiophene-3~acetic acid ethyl ester;
7-chloro-dibenzothiophene-3-acetic acid;
8-methyl-dibenzothiophene-3-acetic acid;
lS 6-chloro-dibenzothiophene-3-acetic acid;
8,9-dichloro-dibenzothiophene-3-acetic acid;
~-methyl-dibenzothiophene-3-acetic acid;
7-methyl-dibenzothiophene-3~acetic acid;
7,8-dichloro-dibenzothiophene-3-acetic acid;
8-chloro-9-methyl-dibenzothiophene-3-acetic acid;
8-chloro-7-methyl-dibenzothiophene-3-acetic acid;
8-fluoro-dibenzothiophene-3-acetic acid;
6,7-dichloro-dibenzothiophene-3-aceti.c acid;
8-ethyl-dibenzothiophene-3-acetic acid;
8-chloro-dibenzothiophene-3-acetic acid dimethylamino-ethyl ester;

'.

- s -8-methyl-dibenzothiophene-3 acetic acid ethyl ester;
8-iodo-dibenzothiophene-3-acetic acid;
8-chloro-N,N-dimethyl-dibenzothiophene-3-acstamide, 8-chloro-dibenzothiophene-3-acetic acid dimethylamino-ethyl ester hydrochloride;
7-chloro-dibenzothiophene-3-acetic acid ethyl ester;
9-chloro-dibenzothiophene-3-acetlc acid ethyl ester;
8-bromo-dibenzothiophene-3-aceti.c acid ethyl ester;
8-chloro-dibenzothiophene 3-propionic acid ethyl ester;
8-chloro-~,~-dimethyl-dibenzo~hiophene-3-ace~ic acid ethyl ester;
8-chloro-~-methyl-dibenzothiophene-3-acetic acid dimethyl-aminoethyl ester;
8-chloro-~-methyl-dibenzothiophene-3-acetamide;
6,7-dichloro-dibenzothiophene-3-acetic acid ethyl sster;
8,9-dichloro-dibenzothiophene-3-acetic acid ethyl ester;
8-~luoro-dibenzothiophene-3-acetic acid ethyl ester;
7,8-dichloro-dibenzothiophene-3 acetic acid ethyl ester;
7~dimethylaminodibenzothiophene-3-acetic acid ethyl ester and the like.

The compound of general formula I, their pharma-ceutically acceptable salts or their acid addition salts are prepared by a process which comprises a) treating a compound of the general formula 414~

R~R2 wherein R, Rl and R2 have the above mentioned meanings, with a dehydrogenating agent, or b) for the pr~para~ion of compounds of formula I, wherein n is 1, X and Y are hydrogen and B is lower alkoxy treating a diazoketone of the general formula ~ ~ ' 1 CO~H--N3N

with a lower alkanol, or c) for the preparation of compounds of formula I, wherein B is hydroxy, hydrolyzing a compound of formula I, wherein B is lower alkoxy or d) for the preparation of compounds of formula I, wherein B is lower alkoxy, esterifying an acid of formula I, wherein B is hydroxy, or a salt thereof, or e) for the preparation of compounds of ~ormula I, wherein A is hydroxy, reducing an ester o~ formula I, wherein B is alkoxy, or .~ - 6 -.~

f) for the preparation of a compound of formula I, wherein R2 is -~H-CO-R4, whereby R3 is lower alkyl and R4 is lower alkoxy, alkylating a compound of formula I, where.in R2 is -CH2-CO-R4 whereby R4 is as above, or g) for the preparation of a compound of formula I, ~5 wherein R2 is -~-CO-R4, whereby R5 is a lower alkyl group and R3 and R4 are as defined above, alkylating a compound of formula I, wherein R2 is -CH-CO-R4 wherein R3 and R4 are as described above, or h) forming pharmaceutically acceptable salts of compounds of formula I, wherein B is hydroxy, or i) forming pharmaceutically acceptable acid addition salts of compounds of formula I, wherein R or Rl is di-lower alkylamino and/or B is di-lower alkylamino-lower alkoxy, or j) resolving a racemic mixture of a compound of formula I~ wherein X and Y are different, intv the optical antipodes.
According to process aspect a) a compound of formula II is treated with a dehydrogenating agent, for example, p-chloranil, o-chloranil, 2,3-dichloro-5,6~dicyano-benzoquinone tDDQ), sulfur, palladium on carbon, lead oxide, ,. ~
~. ~

and the like, in the presence of a solvent, for example, xylene, benæene, toluene, quinoline, dimethylsulfoxide (DMS0), dioxane, dimethylformamide (DMF). The aromatization is carried out at a temperature in the range of from about room temperature to about the reflux temperature of the reaction mixture; preferably, it is carried out at the reflux temperature of the reac-tion mixture. The compound of formula I can be separated from the reaction mixture by known procedures, included among which are, for example, filtration, crystallization, distillationl and the like.
According to process aspect b) a dia20ketone of formula III can be reacted with a lower alkanol. The rearrangement with the alkanol is preferably carried out in the presence of silver ions and at the reflux temperature of the reaction mixture.
According to process aspect c) an ester of formula I can be converted to the corresponding acid, i.e., the compounds of formula I wherein B is hydroxy, by saponification according to known procedures, for example, by reaction with an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like, and subsequent treatment with a mineral acid, for example, a hydrohalic acid such as hydrochloric acid or the like. Additionally, an ester of formula I can be converted to the corresponding acid by treatment with a mineral acid, for example, a hydro-halic acid such as hydrochloric acid or the like, in the presence of an organic solvent such as acetic acid, preferably at the reflux temperature of the reac~ion mixture.
The separation of the desired compound of formula I from the reaction mixture can be e~fected utilizing known techniques such as, for example, filtration, crystallization, distillation and the like.
According to process aspect d) an acid of formula I, wherein B is hydroxy, can be converted to the corresponding ester by known procedures. For instance, (a) an acid of formula I can be reacted with an alkanol such as methanol, ethanol, propanol or the like, in the presence of an acid catalyst at a temperature in the range of from about room temperature to -the reflux temperature of the reaction mixture, or (b) an alkali metal salt of an lS acid of formula I, such as the sodium salt, can be reacted with an alkyl halide utilizing known reaction conditions, for example, in an inert solvent such as benzene, toluene dimethylformamide or the like, at a temperature in the range of from about room temperature to the reflux temperature of the reaction mixture.
According to process aspect e) an ester of formula I can be converted to the corresponding alcohol, e.g., wherein A is hydroxy, by known procedures. For example, an ester of formula I can be treated with a reagent such as lithium aluminum hydride, at a temperature in ~he range of from about room temperature to the reflux 3a - 10~16 -temperature of the reaction mixture. Thereafter, the corresponaing alcohol which is formed can be separated by known procedures.
According to process aspect f) an ester of formula I can be alkylated in the ~-position. This alkyla-tion can be carried out by dissolving the ester in liquid ammonia containing sodium amide and then adding an alkylating agent such as methyl iodide or butyl bromide, to produce the ~-alkylated product.
According to process aspect g) an a-alkylated ester of formula I can again be alkylated using the method as described above.
The starting materials of formula II can be prepared by cyclizing a compound o~ the formula R

R ~ ~ ~V

wherein R, Rl and R2 are as previously described.

r 1 Q 1 6 - 17 ~4~

The cyclization can be effected by thermal cyclization or by utilizing a cyclizing agent, such as polyphosphoric acid, and the like. Preferably, the reaction is carried out at a temperature in the range of form about -20 to about 120. The reaction can be conveniently carried out with or without a solvent. Exemplary of convenient solven~s are acetic acid and the like.

Exemplary of the in-termediates of formula IV are:

3-(4-chloro-phenylthio)-4-oxocyclohexaneacetic acid and ethyl ester thereof;
3-(4-bromo-phenylthio)-4-oxocyclohexaneacetic acid and methyl ester thereof; and the like.

The compounds of formula IV can be prepared by alkylating a compound of the formula R ~ ll V

~ SH

wherein R and Rl are as previously described, with the corresponding haloketocycloalkane compound of the formula ~
Vl H~R2 - 18 - ~ ~$ ~

wherein HAL is halogen and R2 is as previously described, to yield a compound of the formula IV.

The reaction is conveniently carried out in a non-polar solvent, for example, a hydrocarbon, such as benzene, toluene and the like, or a polar solvent, such as dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, an alkanol such as ethanol, and the like. The reaction temperature is not critical Preferably, the reaction is carried out a a temperature in the range of from about room temperatur to about the reflux temperature of the reaction mixture. The molar ratio of the reactants is not critical. Preferably, they are reacted at a l:l molar ratio.

.

The starting materials of formula VI can be prepared by halogenating a compound of the formula ~ Vll wherein R2 is as previously described;
to yield the compound of the formula VI.

The compounds of formula VII are known compounds or can be prepared in an analogous manner to known compounds.

The halogenation is effected utilizing known procedures, for example, utilizing a halogen such as bromine in ether, at a temperature of -10C. Exemplary of such compounds are:
3-bromo 4-ketocyclohexaneacetic acid;
3-bromo-4-ketocyclohexaneacetic acid ethyl ester;

and the like.

The startin~ materials of formula V are known compounds or can be prepared ln an analogous manner to known compounds.
Exemplary of such compounds are:

4-chlorothiophenol;

5-chlorothiophenol; and 4-nitrothiophenol.

The starting materials of formula III can be obtained from the corresponding carboxylic acid. The acid is converted to the acid halide, especially chloride, and then reacted with diazomethane to form the diazoketone.

The compounds of formula I, when B is hydroxy, form according to process aspect h) salts with pharmaceutically acceptable bases. Exemplary of such bases are alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, and the like; alkaline earth hydroxides, such as calcium hydroxide, barium hydroxide and the like; sodium alkoxides, such as sodium ethanolate, potassium ethanolate and the like; organic bases such as piperidine, diethanolamine, N-methylglucamine, and the like. Also included are the aluminum salts of the compounds of formula I, as above.

The compounds of formula I when R or Rl is di-lower alkylamino, and/or B is di-lower alkylamino-lower alkoxy, form according to process aspect i) addition salts with pharmaceutically acceptable ~ - 19 -- 20 - ~

organic or inorganic acids such as hydrohalides, e~g., hydrochloride, hydrobromide, hydroiodide, other mineral acid salts sueh as sulfatel nitrate, phosphate and the like, alkyl-and mono-arylsulfonates sueh as ethanesulfonate, toluenesul-fonate, benzenesulfonate, or the like, other organic acid salts such as acetate, tartrat~, maleate, citrate, benzoate, salicylate, ascorbate and the like.

The compounds of formula I, including the salts of those compounds of formula I which form salts with pharmaceu-tically aeeeptable bases and acids, possess anti-inflammatory, analgesie and anti-rhe~natle activity, and are therefore useful as anti-inflammatory, analgesic and anti-rheumatie agents. The eompounds of formula I also exhibit a significantly low ineidence of uleerogenic activity, which renders them highly desirable as anti-inflammatory, analgesic and anti-rheumatie agents. Their pharmacologically useful activities are demonstrated in warm-blooded animals using standard procedures.

For example, the anti-inflammatory activity is demonstrated in Albino rats of Hart Strain, weighing 125-155 gms. Th~ test animals are given 10 mls. of vehiclel, which eontains the test eompound per kg. of body weight. The animals lHilgar, A.G. and Hummel, D.J.: Endocrine Biossay Data.
No. 1, p. 15, August 1964 ~Cancer Chemotherapy National Service Center, N.I.H.) - 21 ~

are treated daily for 5 consecutive days. Three hours after the first treatment, 0.05 ml. of an 0.5% suspension oE heat killed dessiccated Mycobacterium butyricum in U.SOP. olive oil, which has been steam sterilized for 30 minutes, is injected into the right hind foot of each rat. The paw volume is measured immediately after the injection of the adjuvant and a~ain 96 hours later. The di~ference is recorded as volume of edema. The paw volume is measured by immersion of the paw into a column of mercury to an ink mark exactly at the level of the lateral malleolus. Percent inhibition is calculated by dividing the average control edema minus the average treatment edema by the average control edema times lOO o The percent inhibition is plotted against dose on semi~logarithmic probability paper and the dose required to produce a 30%
reduction in edema is estimated therefrom and is expressed as When 8-chloro~dibenzothiophene-3-acetic acid, which has demonstrated an LD50 of, for example, 775 mg. p.o. in mice, is utilized as the test substance at a dosage of 0003 gm.
p.o., an anti-inflammatory activity is observecl (ED30 = 1.8 mg/kg/day).

The analgesic activity of the compounds of the invention is demonstrated, for example, employing the method which is a modification of that described by Eddy (1950) / ~ol:Ee and MacDonald (1944) and Eddy and Leimbach (1952)o The method determines the reaction time of mice dropped onto a hot plate maintained at 55 ~ 0.5C. Six groups of male mice (5 mice/groupl weighing between 20-30 grams are utilized. The initial reaction time of these miee is determined onee, and the reaetion time of eaeh group is then avera~ed. The miee are then administered the vehiele and/or the eompound to be tested by the oral, intraperitoneal or subcutaneous route. The average reaction time of eaeh group is determined again at 30, 60 and 90 minutes after eompound administration and is compared to controls.
Reaetion time is recorded as percent changes from control. All groups are avera~ed before and after trea~ment. A combined reaction time average (recorded as percent change of reaction time threshhold from controls) for all three periods is plotted against dose on graph paper, and a curve is drawn.
The ED50 is read ~rom this curve.

~hen 8-chloro-dibenzothiophene-3-acetie aeid, whieh has demonstrated an LD50 of~ for examle, 775 mg. p.o. in miee, is utilized as the test substance, analgesic aetivity is observed at an ED50 of 120 mg/kg after oral administration.

The eompounds of formula I, their enantiomers and salts thereof as herein described, have effects qualitatively similar to those of phenylbutazone and indomethacin, known for their therapeutic uses and properties. Thus, the end produets of this invention demonstrate a pattern of activity associated with anti-inflammatory agents of known efficacy and safety.

The compounds of formula I, their enantiomers and salts thereof as herein described, can be incorporated into standard pharmaceutical dosage forms, for example, they are useful for oral or parenteral application with the usual pharmaceutical adjuvant material, for example, organic or inorganic inert carrier materials such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums polyalkylene-glycols, and the like. The pharmaceutical preparations can be employed in a solid form, for example, as tablets, troches, suppositories, capsules, or in liquid form, for example, as solutions, suspensions, or ernulsions.
Pharmaceutical adjuvant materials can be added and include preservatives, stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or to act as buffers. The pharmaceutical preparations can also contain other tnerapeu-tically active substances.

Since the compounds of the invention when X and Y
in formula I are different possess an asymmetric carbon atom, they are ordinarily obtained as recemic mixtures. The resolution of such racemates into the optically active isomers can be carried out according to process aspect r) by known procedures. Some racemic mixtures can be precipitated as eutectics and can thereafter be separated. Chemical resolution is, however, preferred. By this method, diastereomers are formed from the racemic mixture with an optically active resolving agent, for example, an optically active base, such 2~

as d-cl-methylbenzylamine, which can be reacted with the carboxyl group. The formed diastereomers are separated by selective crystallization and converted to the corresponding optical isomer. Thus, the invention covers the reacemates of the compounds of formula I as well as their optically active isomers.

The followinc3 Examples further illustrate the invention.
All temperatures are in degrees Centigrade, unless otherwise stated.

Exa~le 1 Pre aration of 8-chloro- ~ -meth~dibenzothi~ phene-3-acctic acid . P
To a 500 ml. three-necked flask containing 100 ml. of liquid ammonia and 0.009 mol of sodium amide (prepared from 0.2 g. sodium) was added dropwise a solution of 2.6 g. of 8-chlorodibenzothiophene-3-acetic acid ethyl ester in 20 ml.
of ether and 10 ml. of tetrahydrofuran. The solution was stirred for 1 hour and the~
a solution of 1.3 g. of methyl iodide in 20 ml. of ether was added dropwise. After the solution was stirred for 1 hour, 0 . S g. of ammonium ehloride was added andthe ammonia allowed to evaporate. Then the residue was acidified with dilute hydrochloric acid and the oil extracted with ether. The ether was removed and the residue slowly solidified. The solid was crystallized from pentane and yielded 1.5 g. of 8-chloro- ~ -methyldibenzothiophene-3-acetic acid ethyl ester, m.p.
73-75 .

1. 3 G . of 8-chloro- cl -methyldibenzothiophene-3-acetic acid ethyl ester was added to 100 ml . of absolute ethanol containing 0 . 6 g . of potassium hydroxide .
The solution was re~luxed for 3 hours. Then the solvent was removed in vacuo nnd the residue dissolved in 30 ml. of water. The solution was acidified with dilute hydrochloric acid and the oil extracted with ether. The ether was removedand the residue, crystallized from ethyl acetate, yielded 0.9 g. of 8-chloro~
20 methyldibenzothiophene-3-acetic acid, m.p. 190-192.

Example 2 Preparation of 8-ch oro~ -dime~bcnzothiophene-3-acetic llcid To a 500 ml. three-necked flask containing 400 ml. of liquid ammonia and 0.017 mol of sodium amide (prepared from 0.39 g. of sodium) was added dropwise 5 a solut;on of 5 .1 g. of 8-chloro- a -methyldibenzothiophene-3-acetic acid ethyl ester in 40 ml. of tetrahydrofuran. The solution was stirred for 1 hour and then a solution of 2.3 g. of methyl iodide in 50 ml. of ether was added dropwise~ After the addition, the solution was stirred for 3 hours. Then 1.1 g. of ammonium chloride was added and the ammonia allowed to evaporate. The residue was lO acidified with dilute hydrochloric acid and the oil extracted with ether. The ether was removed and the residue, crystallized from pentane, yielded 1.8 g. of 8-chloro- , ~-dimethyldibenzothiophene-3-acetic acid ethyl ester> m.p.
57-61 .

1. 8 G . of 8-chloro- , ~ -dimethyldibenzothiophene-3-acetic acid ethyl ester was added to a solution of 0.4 g. of potassium hydroxide in 100 ml. of ethanol.
After the solution had refluxed for 3 hours, the solvent w~s removed in vacuo.
The residue was dissolved in 75 ml. of water and the solution acidified with dilute hydrochloric acid. The crude acid was extrac$ed with ethyl acetate. The solvent was removed in vacuo and the residue, crystallized from acetonitrile, yielded 0.58 g. of 8-chloro- u,c~-dimethyldibenzothiophene-3-acetic acid, m.p. 198-200.

Example 3 Preparation of 8-chloro- ~ -butyldibenzothiophcne-3-acetic acid To a 500 ml. three-necked f~ask containing 200 ml. of liquid ammonia and O.Q14 mol of sodium amide ~prepared from 0.32 g. of sodium) was added dropwise a solution of 3. 8 g. of 8-chlorodibenæothiophene-3-acetic acid ethyl ester in 40 ml.
of tetrahydrofuran. The solution was stirred for 1 hour and a solution of 1. 8 g. of butyl bromide in 50 ml. of ether was added dropwise. The solution was stirred for 1 hour, 0 . 9 g . of ammonium chloride added and the ammonia allowed to evaporate .
The residue was acidified ~vith dilute hydrochloric acid and the oil extracted with ether. The ether was removed by distillation and the residue remaining (3. 9 g. ) was crude 8-chloro- ~ -butyldibenzothiophene-3-acetic acid ethyl ester.

To a solution of 0. 9 g . of potassium hydroxide in 100 ml . of aicohol was added 3.9 g. of crude 8-chloro- -butyldibenzothiophene-3-acetic ecid ethyl ester.
The solution was refluxed for 3 hours and then the solvent was removed in vacuo.~Yater was added to the residue and the insoluble by-products extracted with ether and the ether discarded. The clear aqueous solution was acidified with dilute hydrochloric acid and the desired product extracted with ethyl acetate. The solvent was removed in vacuo and the residue, after crystallization from acetonitrile, yielded 1 g. of 8-chloro- ~-butyldibenzothiophene-3--acetic acid, m.p. 156-159.

4~

Example 4 Preparntion of 3-bromo-4-oxocyclohexaneacetic acid ethyl ester 74.0 G. of 4-oxocyclohexaneacetic acid ethyl ester and 1200 ml. of anhydrous ether were placed in a 3 l. three-necked flask, provided with a thermometer, 5 nitrogen inlet, dropping funnel, condenser and stirrer. The solution was cooled to -10 by means of a dry ice-acetone bath, and 64 . 0 g . of bromine was added drop-wise over a periQd of 3Q-40 minutes. The resulting colorless solution was washed three times with 100 ml. of water, then t~vo times with 125 ml. of cold saturated sodium bicarbonate solution followed by 100 ml. of water. The combined aqueous 10 solutions were extracted twice wîth 150 ml. of ether. The combined ether extracts were dried over anhydrous magnesium sulfate, and the ether was removed by distillation from a steam bath at atmospheric pressure to give a residue of crude 3-bromo-4-oxocyclohexaneacetic acid ethyl ester, weighing 105 g.

Example 5 15 Preparation of 3- (4-chlorophenylthio)-4-oxocyclohexaneacetic acid ethyl ester _ _ _ _ _ 58 G . of 4-chlorothiophenol and a solution of 26. 5 g. of 8Sg6 potassium hydroxide in 1500 ml. of ethanol were each placed in a 31. three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer. The solution tvas brought to reflux and a solution of 105 g. of crude 3-bromo-4-oxocyclo-20 hexaneacetic acid ethyl es'er in 500 ml. of ethanol was added over a period of onehour to the refluxing solution. After the addition, the solution was stirred at reflux for one hour, cooled to room temperature, and filtered to remove the potassium bromide. After removal of the ethanol in vacuo (steam bath, rotary .. . .

evaporator), 300 ml. of water was added to the residue, the product was e~;tracted three times with 200 ml. of ether and the ether e~;tract dried over anhydrous magnesium sulfate. After removal of cther from a steam bath at atmospheric pressure, the residue, weighing 128 g., was distilled in vacuo. A forerun weigh-ing 28.7 g. was collected at 100-190 (1 mm.), while 76.4 g. of a main fr~ction collected at 190-222 (1 mm . ) . A gas chromatographic determination of the main fraction showed that 3- (4-chlorophenylthio)-4-oxocyclohexaneacetic acid ethyl ester was present.

Example 6 Preparation of 8-chloro-1,2,3,4-tetrahydrodiben~othiophene-3-acetic acid _hyl ester 76.4 G. of the above-distilled 3-(4-chlorophenylthio)-4-oxocyclohe~ane-acetic acid ethyl ester ~bp 190-222/1 mm . ~ was added to 1000 g. of polyphosphoric acid, contained in a 2 l. three-necked flask, provided with a stirrer and con-denser. The mixture was heated on a steam bath for 90 minutes and then poured into a mixture of 1 kilogram of ice and 1 liter of water. The mixture was stirred until the dark oily complex was decomposed and a light yellow color appeared. The product was extracted twice with 500 ml. of ether. The ether extract was washed t-vice with 100 ml. of water, then with 100 ml. of saturated sodium bicarbonate solution, dried over anhydrous potassium carbonate, and distilled at atmosphericpressure from a steam ba~h to remove the ether to give 57.1 g. of residue. A gaschromatogram of this crude residue showed the presence of 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester a~d of bis-(4-chlorophenyl)-disulfide .

~ 30- ~

In order to rcmove the by-product bis (4-chlorophenyl)disulfide, 30. 9 g.
o`f the above crude mixture was added to a 1 liter three-necked flask provided with a condenser and an inlet for nitrogen . A so~ution of 4. 8 g. of sodium hy~lroxide in 250 ml. of ethanol was added, and the resulting solution was refluxed for 1 hour 5 under nitrogen. The ethanol was removed in vacuo (steam bath, rotary evaporator) nnd 200 ml. of w~ter added. The solution was acidificd with dilute hydrochloric acid. After the precipitated 8-chloro-1,2,3,4-tetrahydrodibenzothiophene acetic acid had settled, the supernatant liquid was decanted. 100 Ml. of ether was added to the wet semi-solid acid, and the mixture swirled. The insoluble 8-chloro-1,2,3,4-tetrahydrodibenzothiopheneacetic acid was filtered off, washed with 50 ml. of ether, and dried in a vacuum oven overnight at 50. The yield of 8-chloro-1,2,3,4-tetrahydrodibenzothiophene acetic acid was 26 g.), mp 195-202. Re-esterification was carried out by adding 25.4 g. of the above acid to 400 ml. of ethanol saturated at room temperature with hydrogen chloride.

After the solution was refluxed for 6 hours, the ethanol was removed in vacuo (steam bath, rotary evaporator), and 300 ml. of benzene was added to the residue.
The benzene solution was first extracted twice with 75 ml. of water and then ttvice with 75 ml. of 6% sodium bicarbonate. The benzene solution was dried over anhydrous potassium carbonate and distilled in vacuo to remove the benzene.
The weight of the crude ester was 26.6 g., m.p. 55-60. Crystallization from hexane gave 22.1 g. of pure 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester, m.p. 64-66~'.

Ex~nple 7 Preparation of 8-chloro-dibenzothiophene-3-acetic acid ethyl ester Into a 2 liter threc-necked flask provided with a condenser, stirrer and dropping funnel was added 31.2 g. of 2,3-dichloro-5,6-dicy~o 1,4-benzoquinone and 5Q0 ml. of dioxane. To the solution, heated to reflux, wa9 added at a rapid rate a solution of 21.2 g. of 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester in 500 ml. of dioxane. The solution was refluxed and stirred for 18 hours, cooled to room temperature, and filtered to remove the formed hydro-quinone. The solvent was removed in vacuo (steam bath, rotary evaporator), and the residue was dissolved in 300 ml. of methylene chloride. The solution was filtered, if necessary, and passed through a column containing about 200 g. o alumina (Woelm, grade I). The color of the solution was now a light yellow. The solvent was removed (steam bath, rotary evaporator), and the weight of sticky solid was 18.6 g. The latter was recrystallized from hexane and yielded 14 ~. of8-chloro-dibenzothiophene-3-acetic acid ethyl ester, mp 88-90.

Example 8 Pre~aration of 8-chloro-d,ibenzo iophene-3- cetic acid To a 500 ml. flask, fitted with a condenser and containing a solution of 1.84 g.of sodium hydroxide in 150 ml. of ethanol was added 14 g. of 8-chloro-dibenzothio-phene-3-acetic acid ethyl ester. After the solution was reflu:;ed for 1 hour, the solvent was removed in vacuo (steam bath, rotary evaporator), the residue dissolved in 100 ml. of water, and the aqueous solution acidified with dilute hydro-chloric acid. The 8-chloro-dibenzothiophene-3-acetic acid was removed by filtration, washed ~vith water and dried at 60 in a vacuum oven overnight. The yield of 8-chloro-dibenzothiophene-3-acetic acid, after crystallization from i-propanol, was 8 g., mp 220-221.

Example 9 5 Prcparlltion of 3-(2-chlorophenylthio)-4-ketocyclohexane acetic acid ethyl ester 28 G. of 2-chlorothiophenol and a solution of lO.ô g. of 85% potassium hydroxide in 300 ml. of ethanol were each placed in a 3 liter three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer. The solution was brought to reflux and a solution of 50 . 6 g . of 3-bromo-4-ketocyclo-1 O hexaneacetic acid ethyl ester in 500 ml. of ethanol was added over a period of onehour to the refluxing solution. After the addition, the solution was stirred at reflux for one hour, cooled to room temperature, and filtered to remove the potassium bromide. After removal of the ethanol in vacuo (steam bath, rotovapor), 300 ml. of water was added to the residue, the product was extracted three times 15 with 200 ml. of ether and the ether extract dried over anhydrous magnesium sulfate.
After removal of ether from a steam bath at atmospheric pressure, the residue was distilled in vacuo. A ~orerun was collected at 100-19OD (1 mm), while a main fraction was collected at 190-222 (1 mm). The yield of 3-(2-chlorophenyl-thic)-4-ketocyclohexaneacetic acid ethyl ester from the main fraction was 33 . g g., b.p. 205-215/0.7 mm.

Example 1 0 Preparation of 6-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid eth~l ester _ 33 . 9 G . of the above distilled 3- (2-chlorophenylthio)-4-ketocyclohexane-acetic acid ethyl ester was added to 600 g. of polyphosphoric acid, contained in a 2 liter, three-necked flask, provided with a stirrer and condenser. The mixture was heated on a steam bath for 90 minutes and then poured into a mixture of l kilogram of ice and l liter of waterO The mixture was stirred until the dark oily complex ~vas decomposed and a light yellow color appeared. The product was extracted twice with 500 ml. of ether. The ether ~xtract was washed twice with 100 ml. of water, then with 100 ml. of saturated sodium bicarbonate solution, dried over anhydrous potassium c~rbonate, and distilled at atmospheric pressure from a steam bath to remove the ether. The yield of 6-chloro-1,2 ,3 ~ 4-tetrahydro-dibenzothiophene-3-acetic acid ethyl ester was 8.5 g., b.p. 195-210/0.7 mm, mp 51-53 (pentane).

Exam~le 11 Pre aration of 6-chlcro-dibenzothiophene-3-acetic acid et~yl ester _P . . _ Into a 2 liter three-necked flask provided with a condenser, stirrer and dropping funnel was added 6 g. of 2 ,3-dichloro-5 ,6-dicyano-1 ,4-benzoquinone 20 and 500 ml. of dioxane. To the solution, heated to reflux, was added at a rapid rate a solution of 3.3 g. of 6--chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester in 50 . 0 ml . of dioxane . The solution was refluxed ar.d stirred for 18 hours, cooled to room temperature, and filtered to remove the hydro-quinone. The solvent was removed in vacuo (steam bath, rotary evaporator) and - 34 ~

the residue was dissolved in 300 ml. of methylerle chloride. The solution vas filtered, if nccessary, and passed through a column containing about 200 g. of alumina (Woelm, grade I) . The solvent was removed (steam bath, rotary evaporator) . The resulting solid was recrystallized from hexane and yielded 1. 3 g.
OI` 6-chloro-dibenzothiophene-3-acetic acid ethyl ester, mp 62-64 (hexane).

Example 12 Preparntion of 6-ch oro-dlbenæothiophene-3-acetic acid To a 100 ml. flask, fitted with a condenser and containing a solution of 0. 24 g . of potassium hydroxide in 30 ml. of ethanol was added 1. 3 g. of 6-chloro-dibenzothiophene-3-acetic acid ethyl ester. After the solution was refluxed for 1 hour, the solvent was removed in vacuo (steam bath, rotary evaporator), the residue dissolved in 100 ml. of water, and thc aqueous solution acidified with dilute hydrochloric acid. The 6-chlorodibenzothiophene-3-acetic acid was removed by filtration, washed with water and driecl at 60 in a vacuum oven overnight. The yield of 6-chlorodiben~ot}~iophene-3-acetic acid, after crystallization from aceto-nitrile was 0. 8 g., mp 22.,-228.

Example 1 3 Preparation of 3- (4-i-bu~ ,etocyclohexaneacetic acid ethvl ester 31.4 G. of 4-i-butylthiophenol and a solution of 10.6 g. of 85~; potassium hydroxide in 300 ml. of ethanol were each placed in a 3 liter three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer. The solution was brought to rcflux and a solution of 49 . 5 g . of 3-bromo-4-l;etocyclo-hexaneacetic acid ethyl ester in 500 ml. of ethanol was added over a period of one hour to the refluxing solution. After the addition, the solution was stirred at reflux for one hour, cooled to room temperature, and filtered to remove the potassium bromide. After removal of the ethanol in vacuo (steam bath, rotary evaporator~, 300 ml. of water was added to the residue, the product was extracted three times with 200 ml. of ether and the etheI extract dried over anhydrous magnesium sulfate. After removal of ether from a stcam bath at atmospheric prcssure, the residue was distilled in vacuo. A yield of 42 .S g. of 3- (4-i-butyl-phenylthio)-4-ketocyclohexane acetic acid ethyl ester was obtained, b.p. 205-220/2.0 mm.

Example 14 Preparation of 8-i-butyl-1,2 ,3 ,4-tetrahydrodibenzothio~?hene-3-ac tic acid ethyl ester 42.5 G. of the above distilled 3-(4-i-butylphenylthio)-4-ketocyclohexane acetic acid ethyl ester was added to 700 g. of polyphosphoric acid, contained in a 2 liter three-necked flask, provided with a stirrer and condenser. The mixturewas heated on a steam bath for 90 minutes and then poured into a mixture of 1 kilogram of ice and 1 liter of water. The mixture was stirred until the dark oily comple~ ~vas decomposed and a light yellow color appeared. The product was extracted twice with 500 ml. of ether. The ether extract was washed twice with 100 ml. of water, then with lD0 ml. of saturated sodium bicarbonate solution, dried over anhydrous potassium carbonate, and distilled at atmospheric pressure from a steam bath to remove the ether. The yield of 8-i-butyl-1,2,3,4-tetrahydro-dibenzothiophene-3-acetic acid ethyl ester was 24.4 g., b.p. 195-205/0.7 mm.

Example 15 Preparation of 8-i-butyldibenzothiophene-3-acetic acid ethyl ester Into a 2 liter three-necked flask provided with a condenser, stirrer and dropping funn~l was added 16.6 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone 5 and 200 ml. of xylene. To the solution, heated to reflux, was added at a rapid rate a solution of 10.7 g. of 8-i-buty1-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester in 200 ml. of xylene. The solution was refluxed and stirred for 18 hours, cooled to room temperature, and filtered to remove the hydroquinone.
The solvent was removed in vacuo (steam bath, ro~ary evaporator) and the 10 residue was dissolved in 300 ml. of methylene chloride. The solution was filtered, if necessary, and passed through a column containing about 200 g. of alumina (Woelm, grade I) . The solvent was removed (steam bath, rotary evaporator) . The product was recrystallized from hexane and yielded 4. 7 g. of 8-i-butyldibenzothio-phene-3-acetic acid ethyl ester, b.p. 200-215/0.7 mm.

1 5 Exam~
Prel~aration of 8-i-butyl-dibenzothio~hene 3-acetic acid To a 500 ml. flask: fitted with a condenser and containing a solution of 0.81 g. of potassium hydroxide in 125 ml. of ethanol was added 4.7 g. of 8-i-butyldibenzothiophene-3-acetic acid ethyl ester. After the solution was refluxed for 1 hour, the solvent was removed in vacuo (steam bath, rotary evaporator), the residue dissolved in 100 ml. of water, and the aqueous solution acidified with dilute hydrochloric acid. The product was removed by filtration, washed with water and dried at 60 in a vacllum oven overnight. The yield of 8-i-butyl-dibenz~_ . - ' thiophene-3-acetic acid after crystallization from i-propanol vas 1.5 ~., mp 133-135 (heptane).

Exam~?lc 17 Preparation of 9-chlorodibenzothiophene-3-acetic acid (A) 3-(3-chlorophenylthio)-4-oxocyclohexaneacetic acid ethyl ester.
In a 3-l. three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer were placed 23. 8 g. of 3-chlorothiophenol and a solution of 10. 8 g. of 85% potassium hydroxide in 300 ml. of ethanol. The solution was brought to reflux, and a solution of 43 g. of 3-bromo-4-oxocyclohexaneacetic acid ethyl ester in 250 ml. of ethanol was added over a period of one hour. After theaddition, the solution was stirred at reflw; for one hour, cooled to room temperature and filtered to remove the potassium bromide. After removal of the ethanol in vacuo on the steam bath, 150 ml. of water was added to the residue, the product extracted three times with 100 ml. of ether, and the ether extract was dried o~er anhydrous magnesium sulfate. After removal of the ether from a steam bath at atmospheric pressure, the residue was distilled in vacuo. The yield of 3- (3-chloro-phenylthio)-4-oxocyclohe~aneacetic acid ethyl ester was 12.2 g.; b.p. 195-225/
2 mm.

(B) 9-chloro-1,2,3,4-tetrahydrodibenYothiophene 3-acetic acid ethyl ester.
To 200 g. of polyphosphoric acid contained in a l-l. three-necked flask, provided with a stirrer and condenser was added 8. 0 g. of 3- (3-chlorophenylthio)-4-o~;ocyclohexaneacetic acid ethyl ester. The mixture was heated on a stearn bath for 90 minutes and then poured into a mixture of 200 g. of ice and 200 ml. of Water with stirring, which was continued until the dark olly complex was decomposed and a light yellow color appeared. The product WaS extracted twice With 200 ml.
of ether. The ether extract was washed twice with sn ml. of water and then with 50 ml. of saturated sodium bicarbonate solution. The solution was dried olJer anhydrous potassium carbonate and then filtered. The ether was removed on a steam bath in a rotary evaporator at atmospheric pressure, and the residue was distilled at reduced pressure . At 205-220/2 mm . a yield of 3. 3 g . of 9-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester was obtained.

(C) 9-chlorodibenzothiophene-3-acetic acid ethyl ester.
To a 1-1. three-necked flask provided with a condenser, stirrer and droppin~
funnel was added 11 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and 500 ml. of dioxane. To the solution heated to reflux, was added at a rapid rate a solution of 6 g. of 9-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester in 100 ml. of dioxane. The solution was refluxed and stirred for 24 hours, cooled to room temperature and then filtered to remove the hydroquinone.
The solvent was removed in vacuo on the steam bath, and the residue was dissolvec in 200 ml. of methylene chloride. This solution was passed through a column containing about 150 g. of alumina (~'~loelm, grade 1). The solvent was removed on the steam bath and the residue was crystallized from alcohol. The yield of 9-chlorodibenzothiophene-3-acetic acid ethyl ester was 1.1 g., m.p. 82-84.

(D) 9-chlorodibenzothiophene-3-acetic acid.
To a 100 ml. flask, fitted with a condenser and containin~ a solution of 0.28 g. of potassium hydro~ide in 50 ml. of ethanol was added 1.1 g. of 9-chloro-dibenzothiophene-3-acetic acid ethyl ester. A~ter the solution was refluxed for four hours, the solvent was removed in vacuo on the steam bath, the residue was dissolved in 50 ml. of water, and the aqueous solution was acidified with dilutehydrochloric acid. The product was filtered, washed with 20 rnl. of water, and dried at 60 in a vacuum oven for 12 hours. The yield of 9-chlorodibenzothiophene--3-acetic acid, after crystallization from methanol, was 0. ô g. (m .p . 203-206) .

Example 18 Preparation of 8-methyldibenzothiophene 3-acetic acid (A) 3-(4-methylphenylthio)-4-ketocyclohexanecarboxylic acid ethyl ester.
In a 2 l. three-necked flask provided with a condenser, nitrogen inlet, dropping funnel and stirrer were placed 73.5 g. of p-toluenethiol and a solutionof 33 g. of 85~ potassium hydroxide in 500 ml. of ethar.ol. The solution l,vas brought to reflux, and a solution of 146.4 g. of 3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester in 500 ml. of ethanol was added over a period of one hour. After theaddition, the solution was stirred at reflux for one hour. After removal of the ethanol in vacuo on th~ steam bath, 300 ml. of water was added, and the product was extracted three times with 200 ml. of ether. The ether solution was dried o~rer anhydrous magnesium sulfate, and then the solvent was removed on the steambath. The residue was crystallized from heptane; yield 66 g . of 3- (4-methyl-phenylthio)-4-ketocyclohexanecarboxylic acid ethyl ester, m.p. 87-89.

.

-(B) 8-methyl-1,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid ethyl ester.
To 130 g. of polyphosphoric acid cont~ined in a 500 ml. three-necked flask provided with a stirrer and condenser, was added 13 g. of 3-(4-methylphenylthio)-S 4-ketocyclohexanecarboxylic acid ethyl ester. The mixture was heated on a steam bath for 90 minutes and then poured onto a mixture of 200 g. of ice and 200 ml. of water. The mixture was stirred until the dark oily complex was decomposed, and a light yellow color appeared. The product was extracted with ether, and the solution then washed with wa~er until it was neutral. Af~er drying over 10 anhydrous potassium carbonate, the ether was distilled off on the steam bath, and the residue was crystallized from methanol. The yield of 8-methyl-1,2,3,4-tetra-hydrodibenzothiophene-3-carboxylic acid ethyl ester, m.p. 68-69, was 6 g.

(C) 8-methyldibenzothiophene-3-carboxylic acid ethyl ester.
To a 500 ml. three-necked flask provided with a condenser, stirrer and dropping funnel was added 10 g. of 2 ,3-dichloro-5 ,6-dicyano-1 ,4-benzoquinone (DDQ) and 200 ml. of dioxane. To the solution, heated to reflux, was added at a rapid rate a solution of 5.5 g. of 8-methyl-1,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid ethyl ester in 50 ml. of dioxane. The solution was refluxed and stirred for 20 hours, cooled to room temperature and filtered to remove the hydroquinone. The solvent was rernoved in vacuo on the steam bath, and the residue was dissolved in 100 ml. of methylene chloride. The solution was passed through a column containing about 75 g. of alumina (Woelm, grade I). The solvent was removed, and the residue was crystallized from methanol. The yield of 8-methyldibenzothiophene-3-carboxylic acid ethyl ester was 4. 2 g., m.p . 83-87 .

(D) B-methyldibenzothiophene-3-carboxylic acid.
To a solution of 0 . 73 g. o potassium hydroxide in 50 ml . of ethanol was added 3 . 5 g. of 8-methyldibenzothiophene-3-carboxylic acid ethyl ester. The solution was refluxed for 3 hours. The solvent was removed in vacuo on the steambath, and the crude potassium sal~ was dissolved in 50 ml. of water. The solution ~vas acidified with dilute hydrochloric acid and the product was filtered off and dried. The yield of 8-methyldibenzothiophene-3-carboxylic acid was 2 g., m.p.
290-291 .

(E) 3-chlorocarbonyl- 8-methyldibenzothiophene .
A solution of 3 g. of oxalyl chloride in 50 ml. of benzene was added drop~rise with stirring to a suspension of 3. 5 g. of the crude potassium salt of 8-methyldi-benzothiophene-3-carbo~ylic acid in 100 ml. of benzene. The mixture was filtered and the solvent removed in vacuo on the steam bath. The residue, after crystallization from hexane, yielded 2.5 g. of 3-chlorocarbonyl-8-methyldibenzo-thiophene, m.p. 127-128.

(F) 3-diazomethylcarbonyl-8-methyldibenzothiophene.
A solution of 2.5 g. of 3-chlorocarbonyl-8-methyldibenzothiophene in 75 ml . of ether was added dropwise to a solution of 0. 81 g. of diazomethane in 100 ml. of ether in an ice bath. The solution was stirred overnight, and the ether was removed on the steam bath . The crude product (2 . 5 g . ), 3-diazomethyl-carbonyl-8-methyldibenzothiophene, was used directly in the next step.

,, ', - ` ' . ~,. . . ' ' :

(G) 8-methyldibenzothiophene-3-acetic acid ethyl ester.
To a r~fluxing solution of 2.5 g~. of crude 3-diazomethylcarbonyl-8-methyl-dibenzothiophene in 50 ml. of alcohol was ~dded dropwise, with stirring, a solution of 1. O g . of silver benzoate in 10 ml . of triethylamine . The solution was refluxed until evolution of nitrogen had ceased. The solution was filtered, and the solvent was removed in vacuo on the steam bath. The residue was crystallizedfrom petroleum ether (30-60) to yield 1.3 g. of 8-m~thyldiben~othiophene-3-acetic acid ethyl ester, m.p. 45-48.

(H3 8-methyldibenzothiophene-3-acetic acid.
To a solution of 0. ~7 g. of potassium hydroxide in 50 ml. of alcohol, ~vas added 1.3 g. of o-methyldibenzothiophene-3-acetic acid ethyl ester, and the solution was refluxed for 3 hours. The solvent was removed in vacuo, and the residue was dissolved in 50 ml. of water. The solution was acidified with dilutehydrochloric acid and the product was filtered off and dried. Recrystallization from acetonitrile yielded 0.5 g. of 8-methyldibenzothiophene-3-acetic acid, m.p.
18;~-187 .

Example 19 Preparation of dibenzothiophene-3-aceti_ acid ~A) 3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester.
To a 11. three-necked flask provided with a stirrer, condenser and dropping funnel and containing a solution of 25 . S g. of 4-ketocyclohexaneca~boxylic acid ethyl ester in 450 ml. of anhydrous ether cooled to -10 was added dropwise over 45 minutes 24 g. of bromine. The resulting colorless solution was washed with 3 x 100 ml. of water, then with 2 x 50 ml. of 5% sodium bicarbonate solution and finally with 2 x 100 ml. of water. The ether solution was dried over anhydrous magnesium sulfate and then the solvent was removed on a steam bath. The yield 5 of crude 3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester was 37 g.

(B) 3-phenylthio-4-ketocyclohexanecarboxylic acid ethyl ester.
In a 21. three-necked flask provided with a condenser~ nitrogen inlet, dropping funnel and stirrer, were placed 16 . 5 g. of benzenethiol and a solution of 10 g. of potassium hydroxide in 400 ml. of alcohol. The solution was brought 10 to reflux and a solution of 37 g. of 3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester in 200 ml. of alcohol was added over a period of 1 hour. The reaction mixture was then stirred and refluxed for 1 hour. The solvent was removed on a steam bath at reduced pressure and 200 ml. of water added to the residue. The oil was extracted with ether and the solution dried over anhydrous potassium 15 carbonate. The ether was removed on a steam bath and the residue, on vacuum distillation~ yielded 20 g. of 3-phenylthio-4-ketocyclohexanecarboxylic acid ethyl ester, b.p. 198-210 at 2 mm.

(C) 1,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid ethyl ester.
A mixture of 10 g. of 3-phenylthio-4-ketocyclohexane c~lrboxylic acid ethyl ester and 130 g. of polyphosphoric acid was stirred on a steam bath for 1. 5 hours. It was then poured onto a mixture of 400 g. of ice and 400 ml . of water. The oil was extracted with 2 x 100 ml. of ether and the ether extract - ~4 -washed with 2 x 50 ml. of water and then with 50 ml. of 5% sodium bicarbonate solution. The ether solution was dried over anhydrous potassium carbonate, and the solvent then removed on a steam bath. The crude product was distilled at reduced pressure and yielded 5 g. of 1,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid ethyl ester, b.p. 190-195 at 2 mm.

(D~ Dibenzothiophene-3-carboxylic acid ethyl ester.
To a solution of 2.5 g. of 1,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid ethyl ester in 100 ml. of dioxane was added 4.7 g. of 2,3-dichloro-5,6-di-cyano-1, 4-benzoquinone . The solution was stirred and reflu~ed for 31 hours.
The solution was cooled and the hydroquinone filtered off. The dioxane was removed on a steam bath under reduced pressure. The residue was dissolved in 100 ml. of methylene chloride and the solution passed through a column con-taining about 75 g. of alumina (~Yoelm. grade 1). The solvent ~vas removed on a steam bath and the residue crystallized from hexane. The yield of dibenzo-thiophene-3-carboxylic acid ethyl ester, m.p. 74-78 was 1.7 g.

(E) Dibenzothiophene-3-carboxylic acid potassium salt.
To 200 ml. of alcohol containing 2.7 g. of potassium hydroxide was added 13. 2 g. of dibenzothiophene-3-carboxylic acid ethyl ester and the solution was refluxed, stirred for 4 hours and filtered. The insolube dibenzothiophene-3-car-boxylic acid potassium salt was filtered off and weighed, after drying at 80 in a vacuum oven, 8 . 9 g . The dibenzothiophene-3-carboxylic acid, which can be obtained from the above potassium salt is a known compound ~H. Gilrnan, A.L.
Jacoby and H.A. Pacevitz, J. Org. Chem. 3, 120 (1938)3 .

~ 45 ~

(F) 3~chloroc~1rbonyldibenzothiophene.
To a suspension of ~.9 g. of dibenzothiophene-3-carboxylic acid potassium salt in 200 ml. of benzene was added dropwise with stirring over a period of 30 minutes ~ a solution of 6 . 4 g . of oxalyl chloride in 50 ml . of benzene . The rllixture was stirred and refluxed for two hours. The mixture was filtered and the solvent was removed in vacuo on the steam bath. The residue, 3-chlorocarbonyl-dibenzothiophene ~7.9 g.) was used directly in the next step.

(G) 3-di~zomethylcarbonyldiben~othiophene.
A solution of 7 . 9 g. of crude 3-chlorocarbonyldibenzothiophene in 700 ml .
of ether was added with stirring to a solution of 2.7 g. of diazomethane in 180 ml.
of ether in an ice b~th. The solution was stirred for 7 hours and then the solvent was removed, on a steam bath, to yield the crude 3-diazomethylcarbonyldibenzo-thiophene (7 . 5 g . ) which was used directly in the next step .

(H) Dibenzothiophene-3-acetic acid ethyl ester.
To a refluxing solution of 7 . 5 g. of crude 3-diazomethylcarbonyldibenzo-thiophene in 100 ml. of alcohol was added, dropwise with stirring, a solution of1 g. of silver benzoate in 10 ml. o~ triethylamine. The solution was then refluxed for one hour, filtered, and the solvent was removed in vacuo. The residue, after crystallization from petroleum ether (30-60) yielded 2.7 g. of dibenzothio-2Q phene-3-acetic acid ethyl ester, m.p. 60-62.

a) Dibenzothiophene-3-acetic acid.
To a solution of 0.56 g. of potassium hydroxide in 75 ml . of ethanol was added 2.'1 g. of dibenzothiophene-3-acetic acid ethyl ester. The solution was refluxed 3 hours and the solvent then removed in vacuo. The residue was 5 dissolved in 50 ml. of water, and the solution was acidified with dilute hydro-chloric acid. The solid was filtered off and dried in vacuo at 50. Recrystallization from acetonitrile yielded 1 g. of dibenzothiophene-3-acetic acid, m.p. 174-176.

Example_20 Preparation of 7-chlorodib~nzothiophene-3-acetic acid lo ~A) Dibenzothiophene-3-carboxylic acid ethyl ester 5-oxide.
8.3 G . of chlorine was bubbled into a solution of 23.8 g. of dibenzothio-phene-3~carboxylic acid ethyl ester in 600 ml. of carbon tetrachloride cooled to 5. The solution was poured onto ice, and the mixture was well shaken. The solid was filtered off, dried in vacuum at 50 and then crystallized from aceto-nitrile to yield 11.6 g. of dibenzothiophene~3-carboxylic acid ethyl ester 5-o~ide, m.p. 210-213.

(B) 7-nitrodibenzothiophene-3-carboxylic acid ethyl ester 5-oxide.
To 25û ml. of 90% nitric acid kept at 22 25, 25 g. of dibenzothiophene-3-carboxylic acid ethyl ester 5-oxide was added, in portions. The solution was 20 stirred for 15 minutes and then poured onto ice. The solid was filtered off, washed with water until neutral and dried in a vacuum oven at 50. The solid was crystallized from 1,2-dichloroethane to yield 24.7 g. of 7-nitrodiben~othiophene-3-carboxylic acid ethyl ester 5-oxide, m.p. 245-250.

~C~ 7-aminodiben~othiopllene-3-c~lrbo~;ylic acid cthyl ester hydrochloride.
A mixture of 21.9 g. of 7-nitrodibenzothiophene-3-cnrbo:cylic acid ethyl ester 5-oxide, 250 ml . of acetie acid, and 1.7 g . of 10% palladium on carbon was shaken at an initial pressure of 50 pounds of hydrogen and heated to 60. After 5 one hour the uptake of hydrogen had eeased. The mixture was removed from the hydrogenation apparatus, cooled to room temperature and filtered. After removal of the solvent in vacuo on the steam bath, the residue was dissolved in 300 ml.
of ethyl aeetate, and the produet was preeipitated as the hydrochloride by bubhling in hydrogen chloride. The yield of 7-aminodibenzothiophene-3-earboxylic acid ethyl ester hydrochloride was 17.1 g. (m.p. 260-265) . A small portion, after crystalli ation from methallol, melted at 270-275.

(D) 7-ehlorodibenzothiophene-3-carboxylic acid ethyl ester.
A solution of 28.7 g. of 7-aminodibenzothiophene-3-carboxylic acid ethyl ester hydrochloride in 300 ml. of acetic acid was added at 15 to nitrosylsulfuric acid prepared from 19.4 g. of sodium nitrite and 100 ml. of concentrated sulfuric aeid. The mixture was stirred for 15 minutes and then 1 1. of ether was ac'ded to precipitate the diazonium sulfate. The mixture of the diazonium sulfate and sodium sulfate was filtered off, ~rashed with ether, and air-dried. The mixture was then added, in portions at 5 to a cuprous chloride solution prepared from 9.4 g. of cuprous ehloride, 375 ml. of water and 280 ml. of conc. hydrochloric acid.
After the addition, the contents were heated Oll a steam bath until nitrogen evolution ceased. The solid was filtered off, washed with water and then dried in a vacuum oven. The solid, after crystallization from hexane, yielded 18 g.

of 7-chlorodibenzothiophene-3-carboxylic acid ethyl ester, m.p. 120-122.

- ~8 ~ L3L44 (E) 7-chlorodibenzothiophene-3-carboxylic acid potassium salt.
A solution of 4.1 g. of potassium hydroxide (859i) in 100 ml. of alcohol was added to a solution of 18.1 g. of 7-chlorodibenzothiophene-3-carboxylic acid ethyl ester in 450 ml. of warm ethanol. The combined solutions were stirred and refluxed for 8 hours. After cooling to room temperature, the mixture ~vas filtered to give 16 . 5 g . of the potassium salt .

(F) 3-chlorocarbonyl-7-chlorodibenzothiophene.
A solution of 10.5 g. of oxalyl chloride in 100 ml. of benzene was added, with stirring, to a suspension of 16.53 g. of 7-chlorodibenzothiophene-3-carboxylic acid potassium salt in 100 ml. of benzene. The mixture was stirred and refluxed for two hours and then filtered. On distillation to dryness on the steam bath in vacuo 9 g. of crude 3-chlorocarbonyl-7-chlorodibenzothiophene was obtained as a residue.

(&) 7-chlorodibenzothiophene-3-acetic acid ethyl ester.
A solution of 9 g. of 3-chlorocarbonyl-7-chlorodibenzothiophene in 100 ml~
of dioxane was added dropwise to a solution of 5 . 3 g. of diazomethane in 250 ml.
of ether with cooling in an ice bath. The solution was stirred overnight, and the solvent was then removed by distillation in ~racuo. The residue was dissolved in600 ml. of alcohol, and to the refluxing solution was added dropwise over one hour a soluffon of 1 g. of silver benzoate in 100 ml. of triethylamine. The solution was refluxed for one hour after the addition and then filtered. The solvent was removed by distillation in vacuo from a steam bath and the residue was crystallized from 4~

hexane, yield, 4.8 g. of 7-chlorodibenzothiophene-3-acetic acid ethyl ester, m.p.
68-700 .

(H) 7-chlorodibenzothiophene-3-acetic acid.
To a solution of 1 g. of potassium hydroxide in 75 ml. of alcohol was added 4. 8 g. of 7-chlorodibenzothiophene-3-acetic acid ethyl ester. After renu~ing for 3 hours, the solvent was removed in vacuo on the steam bath, and 50 ml. of water ~vas added to dissolve the residue. The aqueous solution was acidified with hydrochloric acid, and the product filtered off. The solid was crystallizedfrom acetonitrile to yield 1. 7 g. of 7-chlorodibenzothiophene-3-acetic acid, m.p .
o 198-200.

Example 21 Preparation of 7-dimethylaminodibenzothiophene-3-acetic acl_thyl ester (A~ 7-aminodibenzothiophene-3-carboxylic acid ethyl ester hydrochloride A mixture of 24 g. of 7-nitrodibenzothiophene-3-carhoxylic acid ethyl ester 5-oxide, 200 ml. of acetic acid and 2.4 g. of 10% palladium carbon was hydrogenated at 50 at an initial pressure of 50 lbs. After completion of the hydrogenation in 3 hours, the mixture was filtered, and the acetic acid was removed in vacuo (steam bath, rotary evaporator). The residue was dissolved in 250 ml. of ethyl acetate, and hydrogen chloride was bubbl0d into the solution.
The precipitated hydrochloride of 7-aminodibenzothiophene-3-carboxylic acid ethyl ester weighed 20 g.; mp 270-275.

50 ~ ~ r~

(B) 7 dimethylaminodibenzothiophene-3-carboxylic acid ethyl ester A mixture of 7 . 3 g. of 7-aminodibenzothiophene-3-carboxylic acid ethyl ester hydrochloride and 5. 0 g. of trimethyl phosphate were heated at 160 îor 45 minutes. After cooling to room temperature, 75 ml. of ethyl acetate was added, and the solution was extracted with 25 ml. of water. The ethyl acetate wPs removed in vacuo (s,team bath, rotary evaporator), and the residue was cr~stallized from ethanol. The yield of 7-dimethylaminodibenzothiophene-3-carboxylic acid ethyl ester was 2.8 g.; mp 160-162.

(C) 7-dimethylaminodibenzothiophene-3-carboxylic acid potassium salt To a solution of 0. 5 g . of potassium hydroxide in 100 ml . of ethanol was added 2 . 8 g. of 7-dimethylaminodibenzothiophene-3-carboxylic acid ethyl ester .
The solution was stirred and refluxed for 3 hours during which time the potassium salt precipitated. The salt was filtered off, washed with ether alld air dried.
The yield of 7-dimethylaminodibenzothiophene-3-carboxylic acid potassium salt was 1 . 9 g .

(D) 7-dimethylaminodibenzothiophene-3-carbonyl chloride To a suspension of 1.9 g. of 7-dimethylaminodibenzothiophene-3-carboxylic acid potassium salt in 100 ml. of refluxing benzene was added over a period of 20 minutes a solution of 1. 2 g. of oxalyl chloride in 25 ml . of benzene . The solution was then stirred and refluxed for 3 hours. The hot solution was filtered. and the filtrate was distilled to dryness in vacuo (steam bath, rotary evaporator).
The residue of crude 7-dimethylaminodibenzothiophene-3-carbonyl chloride weighed 1. 8 g .

~E) 7-dimethylaminodibenzothiophene-3-acetic acid ethyl ester To a 250 ml. 3-necked flask provided with a stirrer, dropping funnel and condenser was added a solution of 0.7 g. of diazomethane in 50 ml. of ether.
The flask was cooled in an ice bath, and a solution of 1. 8 g. of 7-dimethylamino-dibenzothiophene-3-carbonyl chloride in 50 ml. of anhydrous ether and 50 ml.
of tetrahydrofuran was added dropwise over a pF~riod of I5 minutes. The ice bath was removed and the solution stirred for 2 . 5 hours . After removal of thesol~ent by distillation in vacuo on the steam bath, the residue was crystallizedfrom toluene. The yield of 3-diazomethylcarbonyl-7-dimethylaminodibenzo-thiophene vras 0.3 g; mp 173-175. To a refluxing solution of the diazo compound(0.3 g.) in 50 ml. of alcohol was added dropwise, over 1 hour with stirring, a solution of 1 g. of sil~er benzoate in 10 ml. of triethylarr.ine. The solutionwas filtered and the solvents removed from a steam bath in vacuo. The residue was crystallized from methanol and yielded 50 mg. of 7-dimethylaminodibenzo-thiophene-3-acetic acid ethyl ester; mp 115-120.

Example 22 Preparation of 8-chlorodibenzothiophene-3-acetamide A solution of 2.76 g. of 8-chlorodibenzothiophene-3-acetic acid in 10 ml. of thionyl chloride was stirred for 1 hour and then distilled at reduced pressure at room temperature. The residue of crude 8-chlorodibenzothiophene-3-acet~Jl chloride, m.p. 92-99, was then dissolved in 100 ml. of benxene, and the solution as saturated with ammor.ia. The amide was filtered off, washed with water and - 52 - ~

crystallized from acetic acid. The product, 8-chlorodibenzothiophene-3-acct-amide weighed a g. and melted at ~37-238.

Exam~?le 23 Pre aration of 8-chlorodibenzothiophene-3-ethanol P . . _.
3.05 G. of 8-chlorodibenzothiophene-3-acetic acid ethyl ester was added to 0. 45 g. of lithium aluminum hydride in 100 ml . of ether . The solution was refluxed for one hour and then treated with 2 ml. of water. The solution was filtered and the ether removed from a steam bath. The residue was crystallized from acetonitrile and-yielded 1.1 g. of 8-chlorodibenzothiophene-3-ethanol, m.p. 98-100.

~ am~le 24 reparat~on of 8-chlorodibenzothi_phene-3-acetic acid, 2-dimethylaminoethyl ester hydrochloride_ A mixture of 2.76 g. of 8-chlorodibenzothiophene-3-acetic acid, 3.04 g.

of potassium carbonate, 1.73 g. of dimethylaminoethyl chloride hydrochloride, and 250 ml. of dimethylformamide was stirred and heated at 120 for 4 hours. The solvent was removed in vacuo on the steam bath, and 75 ml. of water added to the residue. The oil was extracted with ethyl acetate and the crude product precipitated as the hydrochloride by the addition of hydrogen chloride. On crystallization from acetone, 1. 5 g. of 8-chlorodibenzothiophene-3-acetic acid 2-dimethylaminoethyl ester hydrochloride, m.p. 179-181, wns obtained.

_xample 25 Tablet Formulation Per Tablet 8-chloro-dibenzothiophene-3-acetic acid 25 mg.
Dicalcium Phosphate Dihydrate, unmilled 175 mg.
Corn Starch 24 mg.
Magnesium Stearate 1 mg.
Total Weight 225 mg.

Procedure:
.
1. 25 Parts of 8-chloro-dibenzothiophene-3-acetic acid and 24 parts of corn starch are mixed together and passed through a No. 00 screen in Model IIJII Fitzmill with hammers forward.

2. This premix is then mixed with 175 parts of dicalcium phosphate and one-half of a part of the magnesium stearate, and passed through a No. lA screen in Model IIJII Fitzmill with knives forward, and slugged.

3. The slugs are passed through a No. 2A plate in a Model IIDII Fitzmill at slow speed with knives forward, and the other one-half of a part magnesium stearate is added.

4. The mixture is mixed and compressed into tablets weigh-ing 225 mg.

Example 26 Capsule Formulation Per Capsule 8-chloro-dibenzothiophene-3-acetic acid 50 mg.
Lactose, U.S.P. 125 mg.
Corn Starch, U.S.P. 30 mg.
Talc, U.S.P. ~
Total Weight 210 mg.

_rocedure:

1. 50 Parts of 8-chloro-dibenzothiophene-3-acetic acid is mixed with 125 parts of lactose and 30 parts of corn starch in a suitable mixer.

2. The mixture is further blended by passing through a Fitzpatrick Comminuting Machine with a No. lA screen with knives forward.
3. The blended powder is returned to the mixer, 5 parts talc are added and blended thoroughly.

4. The mixture is filled into No. 4 hard shell gelatin capsules on a Parke Davis capsulating machine.

.~

Ex ~ 7 Tablet Formulation Per ~'ablet 8-chloro-dibenzothiophene-3-acetic acid 100 mg.
Lactose, U.S,P. 202 mg.
Corn Starch, U.S.P. 80 mg.
Amijel B0111 (trade mark) 20 mg.
Calcium Stearate 8 mg.
Total Weight 410 mg.

Procedure:

1. 100 Parts of 8-chlorodibenzothiophene-3-acetic acid, 202 parts of lactose, 80 parts of corn starch and 20 parts Amijel BOll are blended in a suitable mixer.

2. The mixture is granulated to a heavy paste with water and the moist mass is passed through a No. 12 screen. It is then dried overnight at 110F.

3. The dried granules are passed through a No. 16 screen and transferred to a suitable mixer. The calcium stearate is added and mixed until uniformO

4. The mixture is compressed at a tablet weight of 410 mg.
using tablet punches having a diameter of approximately 3/8".
(Tablets may be either flat or biconvex and may be scored if desired.) ' . .

- 56 ~ 4 lA prehydrolyzed food grade corn starch. Any similar pre-hydrolyzed corn starch may be used.

_xample 28 Suppository Formulation Per 1.3 Gm.
Suppository 8-chloro-dibenzothiophene-3-acetic acid 0.025 mg.
Hydrogenated coconut oil 1.230 mg.
10 Carnauba Wax 0.045 gm.

_rocedure:

l. 123 Parts of hydrogenated coconut oil and 4.5 parts of carnauba wax are melted in a suitahle size glass-lined con-tainer tstainless steel may also be used), mixed well and cooled to 45C~

2. 2.5 Parts of 8 chloro-dibenzothiophene-3-acetic acid, whlch has been reduced to a fine powder with no lumps, is added and stirred until completely and uniformly dispersed.

3. The mixture is poured into suppository molds to yield suppositories having an individual weight of 1.3 gms.

_,i,,~

``; - 57 ~ 4~4 4. The suppositories are cooled and removed from molds, and individually wrapped in wax paper for packaging.
(Foil may also be used.)

Claims (22)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of compounds of the general formula 1 wherein R is hydrogen, halogen, lower alkyl or di-lower alkylamino, R1 is halogen, lower alkyl or di-lower alkylamino, R2 is , wherein A is hydroxy or A is -C-B wherein B is hydroxy, lower alkoxy, amino or di-lower alkylamino- lower alkoxy, Y and X, independently, are hydrogen or lower alkyl; and n is 1 to 7;
when X and Y are different, of their enantiomers;
of salts thereof with pharmaceutically acceptable bases;
and of addition salts thereof with pharmaceutically acceptable acids, which process comprises a) treating a compound of the general formula 11 wherein R, R1 and R2 have the above mentioned meanings, with a dehydrogenating agent or b) for the preparation of compounds of formula I, wherein n is 1, X and Y are hydrogen and B is lower alkoxy treating a diazoketone of the general formula 111 with a lower alkanol, or c) for the preparation of compounds of formula I, wherein B is hydroxy, hydrolyzing a compound of formula I, wherein B is lower alkoxy, or d) for the preparation of compounds of formula I, wherein B is lower alkoxy, esterifying an acid of formula I, wherein B is hydroxy, or a salt thereof, or e) for the preparation of compounds of formula I, wherein A is hydroxy, reducing an ester of formula I, wherein B is alkoxy, or f) for the preparation of a compound of formula I, wherein R2 is , whereby R3 is lower alkyl and R4 is lower alkoxy, alkylating a compound of formula I, wherein R2 is -CH2-CO-R4 whereby R4 is as above, or g) for the preparation of a compound of formula I, wherein R2 is , -whereby R5 is a lower alkyl group and R3 and R4 are as defined above, alkylating a compound of formula I, wherein R2 is wherein R3 and R4 are as described above, or h) forming pharmaceutically acceptable salts of compounds or formula I, wherein B is hydroxy.

i) forming pharmaceutically acceptable acid addition salts of compound of formula I, wherein R or R1 is di-lower alkylamino and/or B is di-lower alkylamino-lower alkoxy, or j) resolving a racemic mixture of a compound of formula I, wherein X and Y are different, into the optically antipodes.

2. A process as claimed in claim 1, wherein a compound of general formula 1' wherein R'1 is halogen or lower alkyl and X and Y are as defined in claim 1, an enantiomer thereof when X and Y are different or a salt with a pharmaceutically acceptable base is prepared from a corresponding compound of formula II
according to embodiment a) and optionally c) or h) to j).

3. A process as claimed in claim 1, wherein a compound of general formula 1"

wherein R'1 is halogen or lower alkyl and X
and Y are as defined in claim 1 or an enantiomer thereof when X and Y are different is prepared from a corresponding compound of formula II
according to embodiment a) of claim 1.

4. A process according to claim 2, wherein a compound of formula I',wherein R'1 is halogen, is prepared from a corresponding compound of formula II according to embodiment a) of claim 1.

5. A process according to claim 3, wherein a compound of formula I'', wherein R'1 is halogen, is prepared from a corresponding compound of formula II according to embodiment a) of claim 1.

6. A process according to claim 1,wherein 8-chloro-.alpha.-methyl-dibenzothiophene-3-acetic acid is prepared from 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester according to embodiments a), f) and c) of claim 1.

7. A process according to claim 1, wherein (+) 8-chloro-.alpha.-methyl-dibenzothiophene-3-acetic-acid is prepared from a corresponding compound of formula II
according to embodiment a), f), c) and j) of claim 1.

8. A process according to claim 1, wherein (-) 8-chloro-.alpha.-methyl-dibenzothiophene-3-acetic acid is prepared from 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester according to embodiments a), f) and c) of claim 1.

9. A process according to claim 1, wherein 8-chloro-dibenzothiophene-3-acetic acid is prepared from 8-chloro-1,2,3,4-tetrahydrodibenzothiophene 3-acetic acid ethyl ester, according to embodiments a) and c) of claim 1.

10. A process according to claim 1 wherein 2-(8-chloro-3-dibenzothienyl) ethanol is prepared from 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester, according to embodiments a) and e) of claim 1.

11. A process according to claim 1, wherein 8-chloro-dibenzothiophene-3-acetamide is prepared from the correspond-ing compound of formula II according to embodiment a) of claim 1.

12. Compounds of the general formula 1 wherein R is hydrogen, halogen, lower alkyl or di-lower alkylamino, R1 is halogen, lower alkyl or di-lower alkylamino, R2 is , wherein A is hydroxy or A is -C-B wherein B is hydroxy, lower alkoxy, amino or di-lower alkylamino- lower alkoxy, Y and X, independently, are hydrogen or lower alkyl; and n is 1 to 7;
when X and Y are different, of their enantiomers; of salts thereof with pharmaceutically acceptable bases;

and of addition salts thereof with pharmaceutically acceptable acids, whenever prepared or produced by the process of Claim 1 or by an obvious chemical equivalent thereof.

13. Compounds of the general formula I' wherein R'1 is halogen or lower alkyl and X and Y are as defined in claim 1, an enantiomer thereof when X and Y are different or a salt with a pharmaceutically acceptable base, whenever prepared or produced by the process of Claim 2 or by an obvious chemical equivalent thereof.

14. Compounds of the general formula I"

wherein R'1 is halogen or lower alkyl and X and Y are as defined in claim 1 or an enantiomer thereof when X and Y are different, whenever prepared or produced by the process of Claim 3 or by an obvious chemical equivalent thereof.

15. A compound of formula I', wherein R'1 is halogen, whenever prepared or produced by the process of Claim 4 or by an obvious chemical equivalent thereof.

16. A compound of formula I'', wherein R'1 is halogen, whenever prepared or produced by the process of Claim 5 or by an obvious chemical equivalent thereof.

17. The compound 8-chloro-.alpha.-methyl-dibenzothiophene-3-acetic acid, whenever prepared or produced by the process of Claim 6 or by an obvious chemical equivalent thereof.

18. The compound (+) 8 chloro-.alpha.-methyl-dibenzo-thiophene-3-acetic-acid, whenever prepared or produced by the process of Claim 7 or by an obvious chemical equivalent thereof.

19. The compound (-) 8-chloro-.alpha.-methyl-dibenzo-thiophene-3-acetic acid, whenever prepared or produced by the process of Claim 8 or by an obvious chemical equivalent thereof.

20. The compound 8-chloro-dibenzothiophene-3-acetic acid, whenever prepared or produced by the process of Claim 9 or by an obvious chemical equivalent thereof.

21. The compound 2-(8-chloro-3-dibenzothienyl) ethanol, whenever prepared or produced by the process of Claim 10 or by an obvious chemical equivalent thereof.

22. The compound 8-chloro-dibenzothiophene-3 acetamide, whenever prepared or produced by the process of Claim 11 or by an obvious chemical equivalent thereof.