NO142865B - ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTIC ACTIVE CARBZOLS - Google Patents

Description

The present invention relates to an analogous method for the production of new therapeutically active carbazoles with the general formula I

where R means hydrogen or methoxy, R means chlorine", bromine, cyano, methylthio or nitro, R 2 means where A means hydroxy, hydroxymethyl or a group

where B means hydroxy, C-^_^-alkyl or di-

methylamino-C 1-7 -Alkoxy, X means hydrogen or methyl, n means 1 or 2 and R 3 means hydrogen or methyl

and salts thereof.

The carbazoles of formula I and the pharmaceutically usable salts thereof are anti-inflammatory, analgesic and anti-rheumatic.

The non-pharmaceutically usable salts can be transferred in a manner known per se to compounds of formula I or to pharmaceutically usable salts thereof.

In relation to the tetrahydrocarbazoles known from DOS No. 2,125,926, the compounds produced by the method according to the present invention are distinguished by having superior anti-inflammatory action.

Within the framework of the invention, the term 'C 17 -alkyl' means straight-chain or branched hydrocarbon groups with 1-7 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, neopentyl, pentyl, heptyl and the like. The term "C^_^-Alkoxy" means lower alkyl ether groups, in which the lower alkyl group has the above meaning, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy and the like.

Compounds of formula I and their salts can be prepared by a method which is characterized in that one

a) reacts with a compound of the general formula II

12 3

where R, R , R and R have the meaning given above, with an aromatizing agent,

b) that in the preparation of an ester of formula I where B means C^_^-Alkoxy, an acid of formula I where B is esterified

means hydroxy,

c) that in the preparation of an acid of formula I, where B means hydroxy, an ester of formula I, where B means C1-7-Alkoxy, is hydrolysed, d) that in the preparation of an alcohol of formula I, where A means hydroxy, reduces an ester of formula I where B is

C1_7~Alkoxy,

e) that in the preparation of a compound of "formula I, where B means dimethylamino-C-3-4-alkyloxy, an acid of formula I is reacted,

where B means hydroxy or a salt thereof with a base with an alkylating agent giving off a dimethylamiho-C 1-7 alkyl group,

after which, if desired, an obtained racemate of formula I is split into the optically active isomers and the desired isomer is isolated,

or that when preparing a salt of a compound of formula I, such a compound of formula I is reacted with a base or an acid or both.

Because of the good pharmacological action, preferred compounds of formula I are those where R means Cl and Br.

.Preferred compounds of the formula I are:

the racemate of 6-chloro-α-methyl-carbazole-2-acetic acid,

(+) 6-chloro-α-methyl-carbazole-2-acetic acid,

(-) 6-chloro-α-methyl-carbazole-2-acetic acid, 2-(6-chloro-2-carbazolyl)propanol,

(+) 2-(6-chloro-2-carbazolyl)-propanol,

(-) 2-(6-chloro-2-carbazolyl)-propanol, 6-chloro-carbazole-2-acetic acid and

6-chloro-9-methyl-carbazole-1-acetic acid.

The compounds of formula II can, by reaction with an aromatizing agent, for example with p-chloranil, o-chloranil, 2,3-dichloro-5,6-dicyanobenzoquinone, sulphur, palladium on carbon, lead oxide and the like, be transferred to the corresponding compound of formula I. This reaction is conveniently carried out in the presence of a solvent, for example xylene, benzene, toluene, quinoline, dimethylsulfoxide, dimethylformamide. The aromatization can be carried out at a temperature between about room temperature and the reflux temperature of the reaction mixture, preferably at the reflux temperature of the reaction mixture The compounds of the formula I can be isolated in a manner known per se, for example by filtration from the reaction mixture.

An acid with the formula I can be transferred to an ester in a manner known per se. Thus, e.g. (a) an acid of formula I is reacted with an alkanol, e.g. methanol, ethanol, propanol and the like, in the presence of an acidic catalyst, e.g. a hydrohalic acid, such as hydrochloric acid or hydrobromic acid or the like, at a temperature between approx. room temperature and the reflux temperature of the reaction mixture, or (b) an alkali metal salt of an acid of formula I, e.g. the sodium salt, is reacted with an optionally substituted alkyl halide in a manner known per se, e.g. in an inert solvent, e.g. benzene, toluene, dimethylformamide or the like, at a temperature between approx. room temperature and the reflux temperature of the reaction mixture.

A compound of formula I, where B means C 1-4 alkoxy, can

is hydrolysed in a manner known per se to form the corresponding compound of formula I where B means hydroxy, e.g. by means of an alkali metal hydroxide, e.g. sodium hydroxide or potassium hydroxide in the presence of a solvent, e.g. an alkanol such as methanol or ethanol. Hydro-lighting can be carried out at a temperature between approx. room temperature

and the reflux temperature of the reaction mixture, preferably at the reflux temperature of the reaction mixture. The compound of formula I can be isolated from the reaction mixture in a manner known per se.

An ester with the formula I can be transferred in a manner known per se to the corresponding alcohol with the formula I, where e.g. A means hydroxy, e.g. by reaction with a reagent, such as lithium aluminum hydride, at a temperature between approx. room temperature and the reflux temperature of the reaction mixture. The resulting alcohol can then be isolated from the reaction mixture in a manner known in oq for seq.

An acid of the formula I, where B means hydroxy or a salt of such an acid with a base can be transferred in a manner known per se to a compound of the formula I, where B means dimethylamino-C₁₋₆₆ alkoxy, f .ex. by reaction with a dimethylamino-C^_7-alkyl halide. The temperature at which this conversion is carried out is not critical. Appropriately, however, the turnover is carried out at a temperature between approx. room temperature and the reflux temperature of the reaction mixture. Appropriately, the reaction is carried out in a polar solvent, such as e.g. dimethylformamide, dimethylsulfoxide or the like. The quantity ratio of the reaction components is not critical, but preferably one works with a quantity ratio of 1:1.

The compounds of formula I, where B is hydroxy, form salts with pharmaceutically usable bases. Examples of such bases are alkali metal hydroxides, e.g. sodium hydroxide, potassium hydroxide and the like, alkaline earth metal hydroxides, e.g. calcium hydroxide, barium hydroxide and the like, sodium alkoxides,

e.g. sodium ethanolate, potassium ethanolate and the like," organic bases, e.g. piperidine, diethanolamine, N-methylglucamine and the like. Aluminum salts of the compounds of formula I can also be prepared.

The compounds of formula 1, where X is methyl, are normally formed in the form of racemic mixtures. The separation of such racemates into the optically active isomers can be carried out using known methods. Some racemic mixtures can e.g. precipitate as eutectic and then separate. However, chemical separation is preferred. With this, diastereomers are formed from the racemic mixture with an optically active resolving agent, such as e.g. an optically active base, such as d-α-methylbenzylamine, which can react with an R-carboxyl group. The diastereomers formed are separated by selective crystallization and then transferred to the corresponding optical isomers. The present invention thus concerns both the racemates of the compounds of formula I as well as their optically active isomers.

The starting compounds of formula II can be prepared as described in DOS 23 37 3402.

The compounds of formula I and their pharmaceutically usable salts have anti-inflammatory, analgesic and anti-rheumatic effects and can thus be used as anti-inflammatory, analgesic and anti-rheumatic agents, all the more so because the compounds of formula I have a very low alucerogenic effect. These valuable pharmacological activities can be determined using standard methods.

The anti-inflammatory effect of the compounds has been investigated in rats by injection into the right hind paw of 0.05 ml of a 0.5% suspension of heat-killed, dried Mycobacterium butyricum in olive oil. The compound to be investigated was administered to the animals for 5 consecutive days. Paw volume was measured stretched and 96 hours after the injection. The difference in the paw volume is the "edema volume". The percentage inhibition is calculated on the basis of results from untreated control animals. The results obtained with representative compounds of the formula I and with some representative compounds, which are described in DOS No. 2,125,926, appear from the table below: It is clear from the test results that the compounds produced by the method according to the invention have superior effects in compared to the known compounds.

Thus, e.g. The 6-chloro-a-methyl-carbazole-2-acetic acid at LD^q of 400 mg p.o. in mice an anti-inflammatory activity with an ED^q of 0.17 mg p.o. at a dosage of 0.03 mg p.o. The same compound also exhibits in mice an anti-pyretic activity with an ED,.q of 15 mg p.o. The compounds of formula I, enantiomers thereof as well as salts, as described above, thus possess qualitatively similar action to phenylbutazone and indomethazine, which are known for their therapeutic use and properties.

Due to the particularly good anti-inflammatory, analgesic and antirheumatic effect of racemic 6-chloro-a-methyl-carbazole-2-acetic acid, (+)-6-chloro-a-methyl-carbazole-2-acetic acid, (-)- 6-chloro-α-methyl-carbazole-2-acetic acid, 6-chloro-carbazole-2-acetic acid, 2-(6-chloro-2-carbazolyl)propanol, (+)-2-(6-chloro-2- carbazolyl)propanol, (-)-2-(6-chloro-2-carbazolyl)propanol and 6-chloro-9-methyl-carbazole-1-acetic acid preferred embodiments of the method according to the invention assume that, as starting materials, with formula II, 6-chloro-α-methyl-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester, 6-chloro-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester and 6-chloro-9- methyl-1,2,3,4-tetrahydro-

carbazole-l-acetic acid ethyl ester.

The compounds of formula I, enantiomers thereof and pharmaceutically acceptable salts can be used as pharmaceuticals,

e.g. in the form of pharmaceutical preparations containing them in mixture with a pharmaceutical organic or inorganic carrier material suitable for enteral or parenteral application.

The method according to the invention is explained in more detail in the following examples.

EXAMPLE 1

Preparation of 6-chloro-α-methylcarbazole-2-acetic acid ethyl ester.

A mixture of 34.9 g of 6-chloro-α-methyl-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester (diastereomer mixture), 350 ml of xylene and 56.0 g of p-chloroanil is heated under exclusion of air, under dry nitrogen and under stirring. After 6 hours of stirring at reflux temperature, the reaction mixture is kept overnight at room temperature. The liquid is decanted through a filter, the residue is triturated with 100 ml of benzene, the liquid is decanted through a filter and this procedure is repeated three times. 300 ml of ether are added to the combined filtrates, the solution is extracted three times with 100 ml portions of 2N sodium hydroxide solution, washed by extraction to neutrality with water and dried over anhydrous magnesium sulfate. After filtration of the drying mixture and evaporation of the solvent, a residue of 35.5 g is obtained. After crystallization from 50 ml of methanol, 14.8 g of 6-chloro-a-methylcarbazole-2-acetic acid ethyl ester is obtained, melting point 106 -107.5°C (43.2%).

In an analogous way, the following compounds can be prepared: If you use 6-chloro-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester instead of (d), you get 6-chloro-carbazole-2-acetic acid ethyl ester, melting point 176-178°C (methanol).

If 6-chloro-1,2,3,4-tetrahydrocarbazole-2-propionic acid ethyl ester is used instead of (d), 6-chloro-carbazole-2-propionic acid ethyl ester is obtained, melting point 149-150.5 °C (methanol).

If 6-methylthio-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester is used instead of (d), 6-methylthio-carbazole-2-acetic acid ethyl ester is obtained.

If 6-cyano-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester is used instead of (d), 6-cyano-carbazole-2-acetic acid ethyl ester is obtained, melting point 157-158° C (methanol).

If 6-nitro-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester is used instead of (d), 6-nitro-carbazole-2-acetic acid ethyl ester is obtained, melting point 164-165°C ( methanol).

In an analogous way, the following carbazoles are prepared from

the corresponding 1,2,3,4-tetrahydrocarbazoles:

6-bromo-carbazole-2-acetic acid ethyl ester, melting point 170 -

170.5°C,

6-chloro-9-methyl-carbazole-.1-acetic acid ethyl ester, melting point 123 - 125°C and

6-Chloro-a,9-dimethyl-carbazole-2-acetic acid ethyl ester, melt-

point 96 - 9 8°C.

E X E M P E" L 2

Preparation of 6-chloro-α-methylcarbazole-2-acetic acid (racemate).

A mixture of 11 g of 6-chloro-α-methylcarbazole-2-acetic acid ethyl ester, 100 ml of ethanol and 100 ml of a 3N sodium hydroxide solution is heated under a nitrogen atmosphere with stirring. After 2 hours at reflux temperature, the reaction mixture is evaporated to dryness under reduced pressure, 300 ml of water and 200 g of ice are added to the mixture and the mixture is made slightly acidic by the addition of concentrated hydrochloric acid. The acidic mixture is extracted three times with 200 ml portions of ether, the combined extracts are washed three times with 100 ml portions of water and dried over anhydrous magnesium sulfate. After filtering off the solvent and evaporating the solvent, 9.8 g (98.2%) of a substance is obtained. After recrystallization from chloroform, 6.2 g (62.0%) of 6-chloro-α-methylcarbazole-2-acetic acid is obtained, melting point 197-198°C. From the mother liquors, 1.6 g of substance are obtained, melting point 195-199°C.

In an analogous way, the following compounds can be prepared:

If 6-chloro-carbazole-2-acetic acid ethyl ester is used instead

for (e), 6-chloro-carbazole-2-acetic acid is obtained, melting point 255-257°C (ethyl acetate).

If 6-bromo-carbazole-2-acetic acid ethyl ester is used instead

for (e), 6-bfom-carbazole-2-acetic acid is obtained, melting point 249-250°C (methanol).

If 6-chloro-9-methyl-carbazole-2-acetic acid ethyl ester is used

instead of (e), 6-chloro-9-methyl-carbazole-2-acetic acid is obtained, melting point 235-236°C (ethyl acetate).

If the racemic 6-chloro-a,9-dimethyl-carbazole-2-acetic acid ethyl ester is used instead of (e), then the racemic 6-chloro-a,9-dimethyl-carbazole-2-acetic acid is obtained , melting point 176-178°C (benzene).

If 6-chlorocarbazole-2-propionic acid ethyl ester is used instead

for (e), 6-chlorocarbazole-2-propionic acid is obtained, melting point 230-231°C (methanol).

If 6-methylthiocarbazole-2-acetic acid ethyl ester is used instead of (e), 6-methylthiocarbazole-2-acetic acid is obtained, melting point 202-204°C (ethyl acetate).

If you use "6-nitrocarbazole-2-acetic acid ethyl ester instead of (e), you get 6-nitrocarbazole-2-acetic acid, melting point 262-264°C (methanol).

EXAMPLE 3

Preparation of (-) 6-chloro-α-methyl-carbazole-2-acetic acid.

A solution of 8.0 g of ( + ) a-methylbenzylamine ([<x]^° + 39°) in 40 ml of acetone is slowly added to a solution of 18.0 g of racemic 6-chloro-a-methyl-carbazole-2- acetic acid in 360 ml of acetone. The mixture is kept at room temperature for 3 days, filtered and the filter cake is washed with a small amount of cold acetone, whereby after drying, 10.6 g of the (+) α-methylbenzylamine salt of (-) 6-chloro-α-methyl-carbazole-2 is obtained -acetic acid, [ct]^<2> + 9.9°. The combined filtrates and washing water are evaporated to dryness and the free acid formed is retained for later separation.

After recrystallization of the salt from 200 ml of acetone, you get

6.0 g substance, [a]-<2>,<2> + 11.1°. After two further recrystallizations of the salt, 1.85 g of substance is obtained, [a]^<2> + 13.2°. After further recrystallization of the salt from acetone, no increase in the specific rotation is observed. Dissolve 1.85 g of the salt in 50 ml of hot methanol. Insoluble material is filtered from the cg solution and poured with stirring into a mixture

of ice and hydrochloric acid. After filtration and drying, 1.2 g of acid is obtained. After crystallization from chloroform, 1.0 g of (-) 6-chloro-a-methyl-carbazole-2-acetic acid is obtained, melting point 198-201°C [a]^<2>

-53.0° (c 1.4 methanol).

EXAMPLE 4

Preparation of ( + ) 6-chloro-a-methyl-carbazole-2-acetic acid.

A solution of 4.3 g of (-) α-methylbenzylamine in 20 ml of acetone is added to a solution of 9.7 g of partially separated 6-chloro-α-methyl-carbazole-2-acetic acid, which was obtained by filtration after previous separation of the racemate. The mixture is kept for 24 hours at room temperature, filtered and the filter cake is washed with cold acetone, whereby after drying, 7.3 g of substance is obtained. After recrystallization twice from acetone, 1.9 g is obtained

of the (-) a-methylbenzylamine salt of ( + ) 6-chloro-a-methyl-carbazole-2-acetic acid, [a]^<2> -13.6°. After further recrystallization from acetone, no increase in the specific rotation is observed. The salt is dissolved in 50 ml of hot acetone, the solution is filtered and poured into 500 ml of dilute hydrochloric acid. After filtration and drying, 1.4 g of substance is obtained. After crystallization from chloroform, 0.9 g of (+) 6-chloro-α-methyl-carbazole-2-acetic acid is obtained, melting point 198-201°C [oc]^<2> + 53.2° (c 1 .33 methanol).

EXAMPLE 5

Preparation of 6-chloro-α-methylcarbazole-2-acetic acid t-butyl ester.

A solution of 2 g of 6-chloro-α-methylcarbazole-2-acetic acid (prepared according to the method according to example 2) in 10 ml of tetrahydrofuran is added dropwise with stirring to a solution of 1.4 g of 1,1-carbonyldiimidazole in 10 ml of tetrahydrofuran. The mixture is heated with stirring to reflux temperature. The mixture is stirred for 1 hour at reflux temperature (carbon dioxide is formed) and then cooled to 25°C. Over a period of 5 minutes, a solution of 0.5 g of sodium t-butoxide, 5 g of t-butyl alcohol and 10 ml of tetrahydrofuran is added. The mixture is then heated for 4 hours at reflux temperature, cooled to room temperature and evaporated to dryness under reduced pressure. The residue is distributed between ether and 2N potassium carbonate solution. The ether layer is separated, washed by extraction with water and dried over anhydrous magnesium sulphate. After filtering the drying agent and evaporating the ether, 2.2 g of substance are obtained. After crystallization from aqueous ethanol, 1.7 g of 6-chloro-α-methyl-carbazole-2-acetic acid tert-butyl ester is obtained, melting point 152-154°C.

EKS EMPEL 6

Preparation of racemic 6-chloro-α-methylcarbazole-2-acetic acid methyl ester.

A mixture of 1 g of 6-chloro-a-methylcarbazole-2-acetic acid (prepared according to the method according to example 1), 100 ml of methanol and 3 drops of concentrated sulfuric acid is stirred and allowed to stand for 24 hours at room temperature. The solution is evaporated to dryness under reduced pressure and the residue is partitioned between ether and a dilute sodium carbonate solution. The ether layer is separated and washed by extraction with water and dried over anhydrous sodium sulphate. After filtering off the drying agent and evaporating the ether, 1.2 g of ester are obtained. After recrystallization from hexane, 0.7 g of racemic 6-chloro-α-methylcarbazole-2-acetic acid methyl ester is obtained, melting point 111-112°C.

EXAMPLE 7

Preparation of 6-chloro-a-methylcarbazole-2-acetic acid-2-dimethyl-amino-ethyl ester.

A solution of 3 g of 6-chloro-α-methylcarbazole-2-acetic acid in 10

ml of dimethylformamide is added with stirring to a mixture of 0.48 g of a 54.5% dispersion of sodium hydride (in mineral oil) in 30 ml of dimethylformamide. The mixture is kept for 1 hour at room temperature and a solution of freshly formed dimethylaminoethyl chloride in 10 ml of dimethylformamide is added dropwise to the flask over a period of 10 minutes. The reaction mixture is then kept under stirring for 4 hours at approx. 70°C. The hot mixture is poured into 300 g of ice and, after the ice has melted, extracted with ether. The ether solution is then extracted first with dilute potassium carbonate solution, then with water and the washed ether solution is dried over anhydrous magnesium sulphate. After filtering off the drying agent and evaporating the ether under reduced pressure, 2.7 g of substance are obtained. After crystallization of the residue from a solution of ether and hexane, 2.1 g of 6-chloro-a-methylcarbazole-2-acetic acid-2-dimethylamino-ethyl ester is obtained, melting point 89-90°C.

EXAMPLE 8

Preparation of the racemic 6-chloro-α-methyl-carbazole-2-acetic acid ethyl ester.

A mixture of 10 g of 6-chloro-a-methyl-carbazole-2-acetic acid and 400 ml of 2 g of hydrogen chloride containing ethanol is kept for 12 hours under a nitrogen atmosphere with stirring at reflux temperature and then overnight at room temperature. After adding 50 ml of benzene, the reaction mixture is evaporated under reduced pressure to dryness, the residue is dissolved in 200 ml of ethanol and then, after adding 2 g of hydrogen chloride, the solution is kept for 5 hours at reflux temperature. After cooling to approx. 50°C and adding 50 ml of benzene, the solution is evaporated to dryness, the residue is dissolved in 400 ml of ether and the ether solution is extracted first with 100 ml of a 0.01 M potassium carbonate solution and then twice with 100 ml portions of water. After drying over anhydrous magnesium sulfate. the drying agent is filtered off and the ether is evaporated, whereby 10.6 g (96%) of substance is obtained. After recrystallization from methanol, 8.1 g of the racemic 6-chloro-α-methyl-carbazole-2-acetic acid ethyl ester (74%), melting point 106-107°C are obtained.

EXAMPLE 9

Preparation of 2-(6-chloro-2-carbazolyl)propanol.

A mixture of 30 ml of ether and 0.5 g of lithium aluminum hydride is added dropwise over a period of 20 minutes with stirring a solution of 1 g of 6-chloro-α-methyl-carbazole-2-acetic acid ethyl ester in 80 ml of ether . The reaction mixture is then kept under stirring at reflux temperature for 10 hours. The reaction mixture is then cooled in an ice bath and 30 ml of cold water is added dropwise, so that the temperature never exceeds +10°C. The mixture is then kept under stirring for 1.5 hours at room temperature, filtered and the filter cake is washed twice with 25 ml portions of ether. The combined filtrates and wash water

dried over anhydrous magnesium sulfate. After filtering off the drying agent and evaporating the ether, 0.8 g (93.3%) is obtained

of a remainder. After recrystallization of the product from benzene, 0.7 g (81.5%) of 2-(6-chloro-2-carbazolyl)propanol is obtained, melting point 170-171.5°C.

EXAMPLE 10

In analogy to the method according to example 15, (-) 6-chloro-Q-methylcarbazole-2-acetic acid is converted to the corresponding optically active 6-chloro-α-methylcarbazole-2-acetic acid ethyl ester. In analogy to the method according to example 16, the optically active 6-chloro-α-methylcarbazole-2-acetic acid ethyl ester is then converted to (+) 2-(6-chloro-2-carbazolyl)propanol, melting point 186-187.5°C (benzene), [a]D 2 2 = +20.6 (c 1.81 methanol).

EXAMPLE 11

In analogy to the method according to example 15, (+) 6-chloro-α-methylcarbazole-2-acetic acid is converted to the corresponding optically active 6-chloro-α-methylcarbazole-2-acetic acid ethyl ester. In analogy' ■

with the method according to example 16, the optically active 6-chloro-α-methyl-carbazole-2-acetic acid ethyl ester is then converted to

(-) 2-(6-chloro-2-carbazolyl)propanol, melting point 186-186.5°C,

' 22

[α] = -20.6 (c 1.6 methanol).

Claims (3)

1. Analogy method for the preparation of therapeutically active new carbazoles with the general formula where R means hydrogen or methoxy, R means chlorine, 2 bromine, cyan, methylthio or nitro, R means where A means hydroxy, hydroxymethyl or a group 0 , where B means hydroxy, C,7 alkoxy or di-li 1 1- C - Bmethylamino-C,_7~ alkoxy, X means hydrogen or methyl, n means 1 or 2 and R 3 means hydrogen or methyl and salts thereof, characterized by a) reacting a compound with the general formula II 12 3 where R, R . acid of formula I, where B means hydroxy, hydrolyzes an ester of formula I, where B means <C>1-7- alkoxy, d) in the preparation of an alcohol of formula I, where A means hydroxy, reduces an ester of formula I, where B means C₁₆₆ alkoxy, e) in the preparation of a compound of formula I, where B means dimethylamino-C₁₆₆ alkoxy, reacts an acid with formula I, where B is hydroxy, or a salt thereof with a base with an alkylating agent which releases a dimethylamino-C 1-7 alkyl group. after which, if desired, an obtained racemate of formula I is split into the optically active isomers and the desired isomer is isolated, or by preparing a salt of a compound of formula 1. reacts such a compound of formula I with a base or an acid or both. 2. Process according to claim 1 for the preparation of a compound of formula I where means chlorine or bromine, characterized in that a compound of formula II is used as starting material where R 2 means chlorine or bromine. 3. Method according to claim 1 for the production of racemic 6-chloro-a-methyl-carbazole-2-acetic acid or its optically active components, characterized in that 6-chloro-a-methyl-1 is used as starting material with formula II, 2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester.