FI74949C - FRAMSTAELLNINGSFOERFARANDE FOER 6-CHLORO-METHYL-CARBAZOLE-2-AETXYXRA. ADDITIONAL TO PATENT 71130 - TILLAEGG TILL PATENT 71130 - Google Patents

Description

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SUOMI FINLAND

(FI) (21) Patent application - Patentansökning 800 * »21 (22) Application date - Ansöknmgsdag 12.02.80

National Board of Patents and Registration (23) Start date -Giltighetsdag 23.07-79

Patent-och registerstyrelsen (41) Publications - Biivit offenttig 12.02.80 (44) Date of publication and date of publication y \ _ 12.87

Ansökan utlagd och utl skriften publicerad (86) Intended application - Int ansökan (32) (33) (31) Privilege requested - Begärd priority 02.03.79 Switzerland-Switzerland (CH) 210 ^ / 79 (71) F. Hoffmann-La Roche & Co. Aktiengesel1schaft, Basel, Switzerland-Switzerland (CH) (72) Willy Zwahlen, Thiirnen, Switzerland-Switzerland (CH) (7 * 0 Oy Kolster Ab (5 **) 6-chloro-06-methyl-i-carbazole Process for the preparation of 2-ethanic acid - Fram-11a ningsförfarande för 6-chloro-OC-methyl-carbazole-2-acetic acid (61) Addition to patent 71130 - Tillägg till patent 71130

The invention relates to a process according to FI patent application 792301 for the preparation of 6-chloro-N-methylcarbazole-2-acetic acids known for their pharmaceutical properties.

Hitherto, this compound has been prepared by treating 6-chloro-es :,-methyl-1,2,3,4-tetrahydrocarbazole-2-acetic acid ethyl ester with a flavoring agent such as p-chloroaniline and hydrolyzing the resulting 6-chloro-cy.-methylcarbazole. -2-acetic acid ethyl ester. A disadvantage of this known method, described in FI patent publication 59244, is the use of an aromatizing agent such as p-chloroaniline, which leads to the formation of undesired by-products, especially difficult-to-use chlorine-containing by-products such as tetrachlorohydroquinone. Another disadvantage of this method is that the flavoring agent cannot be easily removed 2 74949 and can only be regenerated by consumption.

In contrast, according to the present invention, 6-chloro-1'-methyl-carbazole-2-acetic acid can be prepared in good yield without said disadvantages.

The process according to the invention is characterized in that the tetrahydrocarbazole derivative of the formula I

ch3 (i)

\ N / \ ^ \ '/ C00R H ^ COOR

wherein R represents lower alkyl, is aromatized by treatment with chlorine and the resulting carbazole derivative of formula II

^ (II) CH3

/ C 0 ° R

H ^ COOR

wherein R is as defined above, is hydrolyzed and decarboxylated.

Lower alkyl R may be branched or preferably straight chain. Examples of such groups are methyl, ethyl, propyl, isopropyl and butyl, with the first two, especially ethyl, being preferred.

The aromatization of the tetrahydrocarbazole derivative of the formula I is suitably carried out in an aprotic solvent such as toluene, methylene chloride or ethylene chloride, preferably toluene, at an elevated temperature, preferably between room temperature and the reflux temperature of the reaction mixture, while slowly adding chlorine. Preferably, chlorine is added within about 2-8 hours, particularly preferably within about four hours. When methylene chloride is used, the aromatization temperature is suitably between about 3,74949 ° C and, when toluene is used, between about 50 ° C and the reflux temperature of the reaction mixture, preferably 75 ° C.

The carbazole derivative of the formula II can be isolated in a known manner, e.g. by crystallization from the reaction mixture, or used in situ in the subsequent reaction steps of the process according to the invention.

The hydrolysis and decarboxylation of the carbazole derivative of the formula II can be carried out simultaneously in a manner known per se, by treatment with acids, e.g. glacial acetic acid, in the presence of a hydrogen halide, such as hydrochloric acid.

The process according to the invention can be carried out as a discontinuous process or, preferably, as a continuous process.

The starting compound of formula I can be obtained by <X-methyl-3-oxocyclohexanemalonic acid di-lower alkyl ester of formula III

0

/ S

CH3 111

'' ^ COOR

wherein R represents lower alkyl, is suitably reacted with p-chlorophenylhydrazine in an inert, organic solvent such as an alkanol, e.g. ethanol, at a temperature of about 25 to 100 ° C, preferably at room temperature.

Example To a 100 liter reaction vessel is added 2.5 kg of (6-chloro-1,2,3,4-tetrahydro-2-carbazolyl) -methylmalonic acid diethyl ester and 75 l of toluene. While stirring, heat to 75 ° C and evacuate the boiler to -0.06 MPa. 940 g of gaseous chlorine are slowly passed in over four hours.

The reaction solution is cooled to 20 ° C. Add 10 L of deionized water. The pH of the aqueous phase is adjusted to pH 8-9 with 1.25 kg of sodium bicarbonate and the aqueous phase is separated. 10 l of deionized water are added to the toluene phase, the mixture is stirred and the aqueous phase is separated. The combined aqueous phases are extracted with 15 l of methylene chloride. The methylene chloride phase is evaporated in vacuo, the toluene phase is added and concentrated in vacuo to a final volume of 5 l. It is then cooled to 0 ° C and stirred overnight at this temperature. The product is sucked off and washed with 1 l of toluene. After drying overnight at 60 [deg.] C., 2.1 kg (85% of theory) of (6-chloro-2-carbazolyl) -methylmalonic acid diethyl ester are obtained, m.p. 134-136 ° C.

The mother liquors from several batches are concentrated to 1/10 of their volume. After crystallization, an additional 170 g (6.8%) of product are obtained per batch.

A mixture of 247 g of (6-chloro-2-carbazolyl) -methyl-malonic acid diethyl ester, 1.9 l of glacial acetic acid and 1.9 l of 6N hydrochloric acid is refluxed overnight with stirring, and the resulting black solution is cooled to room temperature. The solid formed is filtered off, washed with acetic acid / water (1/1) and water and dried. A 192 g portion of the crude 6-chloro-.beta.-methylcarbazole-2-acetic acid obtained is dissolved in 1.2 liters of 1N potassium hydroxide, the solution is extracted with four 300 ml portions of diethyl ether and acidified by adding 100 ml of concentrated hydrochloric acid, while cooling in an ice bath. Stir for 15 minutes, filter the precipitated solid, wash with water and dry. 167.7 g of product are obtained. The final purification is carried out by crystallization from 4.7 l of boiling 1,2-dichloroethane with 8.0 g of activated carbon. The solution is cooled overnight, the crystals are filtered off, washed with dichloroethane and dried. 103.8 g (57.3% of theory) of solid white δ-chloro-O-methylcarbazol-2-acetic acid are obtained, m.p. 198.5-201 ° C.

The starting material can be prepared as follows: 2.5 g of sodium are added to 325 ml of ethanol, a solution of 200 g of methylmalonic acid podiethyl ester is added within 5 minutes and the mixture is stirred for one hour. Within 1 hour, a solution of 100 g of 2-cyclohexan-1-one in 130 ml of ethanol is then added. The mixture is stirred overnight. After adding 20 ml of acetic acid, the mixture is evaporated, the resulting oil is dissolved in 1.31 liters of diethyl ether and the solution is washed with water. The ether solution is dried, filtered and dried once more, the ether is removed under reduced pressure and the residual oil is distilled off in vacuo. 211.5 g (75.4% of theory) of N-methyl-3-oxocyclohexanemalonic acid podiethyl ester are obtained, boiling point 129-130 ° C / 0.2.

A mixture of 100 g of n-methyl-3-oxocyclohexane-malonic acid diethyl ester, 66.3 g of p-chlorophenylhydrazine hydrochloride and 300 ml of ethanol is stirred for 1 1/2 hours and then refluxed for 1 1/2 hours. The mixture is left to stand overnight at room temperature, then cooled in an ice bath and the crystals are filtered off. The filter cake is dried, washed with ice-cold ethanol and then hexane / ethanol (1/1) and dried. The solid formed (97.1 g) is stirred in an ice bath under nitrogen with 500 ml of water, filtered, washed with water and dried. 78.8 g (56.5% of theory) of (6-chloro-1,2,3,4-tetrahydro-2-carbazolyl) -methylmalonic acid diethyl ester are obtained, m.p. 129-130 ° C.

Claims (3)

74949 6 Process for the preparation of 6-chloro-10-methylcarbazole-2-acetic acid according to FI patent application 792301, characterized in that the tetrahydrocarbazole derivative of the formula I n "amoj ^ coor H 2 COOR in which R represents lower alkyl is aromatized by treatment with chlorine and the resulting carbazole derivative of the formula II is hydrolyzed and decarboxylated, wherein R is as defined above. Process according to Claim 1, characterized in that a compound of the formula I is used in which R is ethyl. Process according to Claim 1 or 2, characterized in that the aromatization is carried out in an aprotic solvent, in particular toluene.